Pharmacologically active pyrazolopyridine compounds

ABSTRACT

The invention relates to novel pyrazolopyridine compounds useful as a diuretic, antihypertensive agaent, for renal insufficiency, for thrombosis, and as a cardiotonic agent.

This is a division of application Ser. No. 07/202,526, filed on June 6,1988 now U.S. Pat. No. 4,925,849.

The present invention relates to novel pyrazolopyridine compound and apharmaceutically acceptable salt thereof.

More particularly, it relates to novel pyrazolopyridine compound and apharmaceutically acceptable salt thereof, which are useful for diuretic,antihypertensive agent, remedy for renal insufficiency, remedy forthrombosis and cardiotonic agent, to processes for preparation thereof,to pharmaceutical composition comprising the same, and to a method forusing the same therapeutically in human being and animals.

Accordingly, one object of the present invention is to provide the novelpyrazolopyridine compound and a pharmaceutically acceptable saltthereof, which are useful for diuretic, antihypertensive agent, remedyfor renal insufficiency, remedy for thrombosis and cardiotonic agent.

Another object of the present invention is to provide processes for thepreparation of the novel pyrazolopyridine compound or a salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said pyrazolopyridinecompound or a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method forusing said pyrazolopyridine compound as diuretic, antihypertensiveagent, remedy for renal insufficiency, remedy for thrombosis andcardiotonic agent, which comprises administering said pyrazolopyridinecompound to human being or animals.

The novel pyrazolopyridine compound of the present invention can beshown by the following formula (I). ##STR1## wherein R¹ is lower alkyl,aryl which may have one or more suitable substituent(s) or aheterocyclic group,

R² is a group of the formula: ##STR2## (wherein R⁴ is protected amino orhydroxy and R⁵ is hydrogen or lower alkyl);

cyano;

a group of the formula:

    --A--R.sup.6

(wherein R⁶ is an acyl group, and A is lower aliphatic hydrocarbon groupwhich may have one or more suitable substituent(s));

amidated carboxy;

amino or protected amino; and

R³ is hydrogen, lower alkyl, lower alkoxy or halogen.

The object compound (I) or a salt thereof of the present invention canbe prepared by the following reaction schemes. ##STR3## wherein R¹, R²,R³, R⁴, R⁵, R⁶ and A are each as defined above,

R_(a) ¹ is aryl having nitro,

R_(b) ¹ is aryl having amino,

R_(c) ¹ is aryl having protected amino,

R_(a) ² is amidated carboxy,

R_(b) ² is amino or protected amino,

R_(c) ² is protected amino,

R_(a) ⁶ a is protected carboxy,

R_(b) ⁶ is amidated carboxy,

R⁷ is lower alkanoyl,

R⁸ is esterified carboxy,

R_(N) ¹ is N-containing heterocyclic group having hydroxy(lower)alkyl,

R_(N) ² is N-containing heterocyclic group having loweralkoxy(lower)alkyl,

R_(N) ³ is N-containing heterocyclic group having acyloxy(lower)alkyl,

R_(N) ⁴ is N-containing heterocyclic group having protected carboxy,

R_(N) ⁵ is N-containing heterocyclic group having carboxy,

A¹ is lower alkenyl which may have one or more suitable substituent(s),

A_(a) ¹ is lower alkenyl,

A_(b) ¹ is lower alkenyl having halogen,

A² is lower alkynyl, and

X is a leaving group.

Regarding the starting compounds, some of the compounds (IV) and (IX)are novel and they can be prepared according to the processes disclosedin Preparations 1 and 2 described later or similar manners thereto.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional ones and include a metal salt such as an alkali metalsalt (e.g. sodium salt, potassium salt, etc.) and an alkaline earthmetal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt,an organic base salt (e.g. trimethylamine salt, triethylamine salt,pyridine salt, picoline salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.acetate, trifluoroacetate, maleate, tartrate, fumalate,methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), aninorganic acid salt (e.g. hydrochloride, hydrobromide, hydriodide,sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine,aspartic acid, glutamic acid, etc.), and the like.

In the above and following descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unlessotherwise indicated.

The term "higher" is intended to mean 7 to 20 carbon atoms unlessotherwise indicated.

Suitable "lower aliphatic hydrocarbon group" may include lower alkyl,lower alkenyl, lower alkynyl as explained below and the like.

Suitable "lower alkyl" may include straight or branched ones such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or thelike, in which the preferred one may be (C₁ -C₄)alkyl and the morepreferred one may be methyl, ethyl, propyl and isopropyl.

Suitable "lower alkenyl" may include straight or branched ones such asvinyl, 1-methylvinyl, 2-methylvinyl, 1-propenyl, 2-propenyl, 1-butenyl,2-methyl-1-propenyl, 1,3-butadienyl, 1-pentenyl, 4-pentenyl, 1-hexenyl,1,4-hexadienyl, 5-hexenyl or the like, in which the preferred one may be(C₂ -C₄)alkenyl and the more preferred one may be vinyl, 1-methylvinyl,2-methylvinyl and 1,3-butadienyl.

Suitable "lower alkynyl" may include straight or branched ones such asethynyl, 1-propynyl, 1-methylethynyl, 2-butynyl, 2-methyl-3-butynyl,2-pentynyl, 1-hexynyl or the like, in which the preferred one may be (C₂-C₄)alkynyl and the more preferred one may be ethynyl.

Aforesaid "lower aliphatic hydrocarbon group" may have one or more(preferably one to three) suitable substituent(s) such as halogen (e.g.chloro, bromo, fluoro, iodo) or the like.

Suitable "protected amino" may include amino substituted with theconventional amino protective group such as lower alkylamino (e.g.methylamino, ethylamino, propylamino, butylamino, t-butylamino,pentylamino, hexylamino, etc.), di(lower)alkylamino (e.g. dimethylamino,diethylamino, N-ethylpropylamino, dibutylamino, N-(t-butyl)pentylamino,dihexylamino, etc.), acylamino explained below or the like.

Suitable "acylamino" may include ureido; lower alkanoylamino (e.g.formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino,pivaloylamino, hexanoylamino, etc.), lower alkoxycarbonylamino (e.g.methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,t-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino,etc.), lower alkoxycarbonyl(lower)alkanoylamino (e.g.methoxycarbonylacetylamino, ethoxycarbonylacetylamino,2-(propoxycarbonyl)propionylamino, 4-(t-butoxycarbonyl)butyrylamino,2-(butoxycarbonylmethyl)propionylamino,2-methyl-2-(pentyloxycarbonylmethyl)propionylamino,6-hexyloxycarbonylhexanoylamino, etc.), lower alkanesulfonylamino (e.g.methanesulfonylamino, ethanesulfonylamino, propanesulfonylamino,butanesulfonylamino, t-butanesulfonylamino, pentanesulfonylamino,hexanesulfonylamino, etc.) and the like.

Said "lower alkanoylamino" may have suitable substituent(s) such asdi(lower)alkylamino (e.g. dimethylamino, N-methyl-N-ethylamino,dipropylamino, di-t-butylamino, N-pentyl-N-hexylamino, etc.); cyclicamino group (e.g. piperidino, etc.) which may have lower alkyl; or thelike, and suitable examples of said "lower alkanoylamino having suitablesubstituent(s)" may include lower alkanoylamino havingdi(lower)alkylamino [e.g. dimethylaminocarbonylamino,2-dimethylaminoacetylamino, 2-(N-methyl-N-ethylamino)acetylamino,2-dimethylaminopropionylamino, 3-dipropylaminobutyrylamino,2-(di-t-butylamino)-2-methylpropionylamino,2-dimethylaminomethyl-2-methylpropionylamino,6-(N-pentyl-N-hexylamino)hexanoylamino, etc.];

lower alkanoylamino having cyclic amino group which may have lower alkyl[e.g. piperidinocarbonylamino, 2-piperidinoacetylamino,2-(2-methylpiperidino)acetylamino, 2-(2-ethylpiperidino)acetylamino,2-piperidinopropionylamino, 3-(2-ethylpiperidino)butyrylamino,2-(4-ethylpiperidino-2-methylpropionylamino,2-piperidinomethyl-2-methylpropionylamino,6-(3-propylpiperidino)hexanoylamino, etc.]; and the like.

In aforesaid "acylamino", the preferred one may be ureido, (C₁-C₄)alkanoylamino, (C₁ -C₄)alkoxycarbonyl(C₁ -C₄)alkanoylamino, di(C₁-C₄)alkylamino(C₁ -C₄)alkanoylamino, (C₁ -C₄)alkylpiperidino(C₁-C₄)alkanoylamino, (C₁ -C₄)alkoxycarbonylamino, (C₁-C₄)alkanesulfonylamino, (C₁ -C₄)alkylamino and di(C₁ -C₄)alkylamino, inwhich the more preferred one may be ureido, acetylamino,2-(ethoxycarbonyl)acetylamino, 2-dimethylaminoacetylamino,2-(2-ethylpiperidino)acetylamino, methoxycarbonylamino,methanesulfonylamino, methylamino and dimethylamino.

Suitable "an acyl group" may include lower alkanoyl (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, etc.);carboxy; protected carboxy; and the like.

Suitable examples of aforesaid "protected carboxy" may be esterifiedcarboxy, in which suitable esterified carboxy may include loweralkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,etc.) which may have N-containing heterocyclic group as explained belowand the like;

amidated carboxy, in which suitable amidated carboxy may includeN-(lower)alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl,N-hexylcarbamoyl, etc.);

N-(higher)alkylcarbamoyl (e.g. N-heptylcarbamoyl,N-(2-methylheptyl)carbamoyl, N-nonylcarbamoyl, N-decanylcarbamoyl,N-tricyclo[3.3.1.1³,7 ]decanylcarbamoyl, N-undecanylcarbamoyl,N-(bicyclo[4.3.2]undecanyl)carbamoyl, N-dodecanylcarbamoyl,N-tridecanylcarbamoyl, N-tetradecanylcarbamoyl, N-pentadecanylcarbamoyl,N-hexadecanylcarbamoyl, N-heptadecanylcarbamoyl, N-octadecanylcarbamoyl,N-nonadecanylcarbamoyl, N-icosanylcarbamoyl, etc.);

N,N-di(lower)alkylcarbamoyl [e.g. N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamcyl, N,N-dipropylcarbamoyl,N,N-di(t-butyl)carbamoyl, N-pentyl-N-hexylcarbamoyl, etc.];

N-lower alkyl-N-ar(lower)alkylcarbamoyl (e.g.N-methyl-N-benzylcarbamoyl, etc.); a group of the formula:

    --COR.sub.N

(wherein R_(N) is N-containing heterocyclic group which may have one ormore suitable substituent(s), in which N-containing heterocyclic groupR_(N) may contain the other hetero atom(s) such as N, O or S in itsring.

Suitable "N-containing heterocyclic group" may include saturated orunsaturated, monocyclic or polycyclic heterocyclic group such as

unsaturated 3 to 8-membered (more preferably 5 to 7-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,azepinyl (e.g. 1H-azepinyl, etc.) pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.) etc.;

saturated 3 to 8-membered(more preferably 5 to 7membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), forexample, perhydroazepinyl (e.g. perhydro-1H-azepinyl, etc.)pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;

saturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, 7-azabicyclo[2.2.1]heptyl,3-azabicyclo[3.2.2]nonanyl, etc.;

unsaturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.),etc.;

saturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered(more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.; in which the preferred one may includesaturated 3 to 8 membered heteromonocyclic group containing 1 to 4nitrogen atom(s),

saturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), and

saturated 3 to 8 membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s).

"N-containing heterocyclic group" thus defined may have one or moresuitable substituent(s) such as lower alkyl as mentioned above;hydroxy(lower)alkyl (e.g. hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxybutyl, 1-methyl-1-hydroxymethylethyl,4-hydroxypentyl, 3-hydroxyhexyl, etc.); lower alkoxy(lower)alkyl (e.g.methoxymethyl, 2-methoxyethyl, 1-ethoxyethyl, 3-propoxypropyl,2-(t-butoxy)butyl, 5-pentyloxypentyl, 3-hexyloxyhexyl, etc.);acyloxy(lower)alkyl such as lower alkanoyloxy(lower)alkyl (e.g.acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl,3-propionyloxypropyl, 2-butyryloxybutyl, 4-pivaloyloxypentyl,6-hexanoyloxyhexyl, etc.) or the like; protected carboxy such as loweralkoxycarbonyl as mentioned above; carboxy; or the like.

In aforesaid "N-containing heterocyclic group which may have one or moresuitable substituent(s)", the more preferred one may include piperidinowhich may have 1 to 4 suitable substituent(s) selected from a groupconsisting of (C₁ -C₄)alkyl, hydroxy(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy(C₁-C₄)alkyl, (C₁ -C₄)alkanoyloxy(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl andcarboxy (e.g. piperidino, 2-methylpiperidino, 2-ethylpiperidino,3-ethylpiperidino, 4-ethylpiperidino, 2-propylpiperidino,4-isopropylpiperidino, 2-butylpiperidino, 3-(t-butyl)piperidino,4-pentylpiperidino, 2-hexylpiperidino, 2,2,6,6-tetramethylpiperidino,2,2-dimethyl-6,6-diethylpiperidino, 2-hydroxymethylpiperidino,3-hydroxymethylpiperidino, 2-(1-hydroxyethyl)piperidino,2-(2-hydroxyethyl)piperidino, 3-(2-hydroxyethyl)piperidino,4-(2-hydroxyethyl)piperidino, 2-(3-hydroxypropyl)piperidino,3-(2-hydroxybutyl)piperidino,2-(1-methyl-1-hydroxymethylethyl)piperidino,4-(4-hydroxypentyl)piperidino, 2-(3-hydroxyhexyl)piperidino,2-methoxymethylpiperidino, 2-(2-methoxyethyl)piperidino,2-(1-ethoxyethyl)piperidino, 3-(3-propoxypropyl)piperidino,4-{2-(t-butoxy)butyl}piperidino, 2-(5-pentyloxypentyl)piperidino,3-(3-hexyloxyhexyl)piperidino, 2-acetoxymethylpiperidino,3-(1-acetoxyethyl)piperidino, 2-(2-acetoxyethyl)piperidino,3-(2-propionyloxyethyl)piperidino, 4-(3-propionyloxypropyl)piperidino,2-(2-butyryloxybutyl)piperidino, 3-(4-pivaloyloxypentyl)piperidino,2-(6-hexanoyloxyhexyl)piperidino, 2-methoxycarbonylpiperidino,2-ethoxycarbonylpiperidino, 2-propoxycarbonylpiperidino,3-butoxycarbonylpiperidino, 4-(t-butoxycarbonyl)piperidino,2-pentyloxycarbonylpiperidino, 2-hexyloxycarbonylpiperidino,2-carboxypiperidino, 3-carboxypiperidino, 4-carboxypiperidino,2-(2-hydroxyethyl)-3-methylpiperidino,2-(2-hydroxyethyl)-4-carboxypiperidino, etc.);

pyrrolidin-1-yl which may have (C₁ -C₄)alkoxy(C₁ -C₄)alkyl (e.g.pyrrolidin-1-yl, 2-methoxymethylpyrrolidin-1-yl,2-(2-methoxyethyl)pyrrolidin-1-yl, 2-(1-ethoxyethyl)pyrrolidin-1-yl,3-(3-propoxypropylpyrrolidin-1-yl, 3-{2-(t-butoxy)butyl}pyrrolidin-1-yl,2-(5-pentyloxypentyl)pyrrolidin-1-yl,2-(3-hexyloxyhexyl)pyrrolidin-1-yl, etc.);

perhydroazepin-1-yl (e.g. perhydro-1H-azepin-1-yl, etc.);

piperazin-1-yl which may have (C₁ -C₄)alkyl (e.g. piperazin-1-yl,2-methylpiperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl,2-ethylpiperazin-1-yl, 3-propylpiperazin-1-yl,4-isopropylpiperazin-1-yl, 2-butylpiperazin-1-yl,3-(t-butyl)piperazin-1-yl, 4-pentylpiperazin-1-yl,4-hexylpiperazin-1-yl, etc.);

morpholino; 7-azabicyclo[2.2.1]heptan-7-yl;3-azabicyclo[3.2.2]nonan-3-yl; and the like, and the most preferred onemay include piperidino, 2-methylpiperidino, 2-ethylpiperidino,3-ethylpiperidino, 4-ethylpiperidino, 2-propylpiperidino,2,2,6,6-tetramethylpiperidino, 2-hydroxymethylpiperidino,2-(2-hydroxyethyl)piperidino, 4-(2-hydroxyethyl)piperidino,2-methoxymethylpiperidino, 2-(2-methoxyethyl)piperidino,2-acetoxymethylpiperidino, 2-(2-acetoxyethyl)piperidino,2-ethoxycarbonylpiperidino, 2-carboxypiperidino, pyrrolidin-1-yl,2-methoxymethylpyrrolidin-1-yl, perhydro-1H-azepin-1-yl,4-methylpiperazin-1-yl, morpholino, 7-azabicyclo[2.2.1]heptan-7-yl,3-azabicyclo[3.2.2]nonan-3-yl, and the like.

Suitable "N-substituted amine" may include lower alkylamine (e.g.methylamine, ethylamine, isopropylamine, butylamine, pentylamine,hexylamine, etc.);

higher alkylamine (e.g. heptylamine, 2-methylheptylamine, nonylamine,decanylamine, tricyclo[3.3.1.1³,7 ]decanylamine, undecanylamine,bicyclo[4.3.2]undecanylamine, dodecanylamine, tridecanylamine,tetradecanylamine, pentadecanylamine, hexadecanylamine,heptadecanylamine, octadecanylamine, nonadecanylamine, icosanylamine,etc.);

di(lower)alkylamine [e.g. dimethylamine, diethylamine,N-methylethylamine, dipropylamine, di(t-butyl)amine, N-pentylhexylamine,etc.];

N-lower alkyl-ar(lower)alkylamine (e.g. N-methylbenzylamine, etc.); acompound of the formula:

    H--R.sub.N

(wherein R_(N) is as defined above)

Suitable "aryl" may include phenyl, naphthyl, indenyl, anthryl and thelike and said "aryl" may have one or more suitable substituent(s) suchas halogen (e.g. fluoro, chloro, bromo, iodo), lower alkoxy (e.g.methoxy, ethoxy, propoxy, t-butoxy, pentyloxy, hexyloxy, etc.), nitro,amino, protected amino as mentioned before or the like.

The preferred examples of "aryl which may have one or more suitablesubstituent(s)" may include phenyl which may have 1 to 3 suitablesubstituent(s) selected from a group consisting of halogen, (C₁-C₄)alkoxy, nitro, amino, (C₁ -C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino, (C₁ -C₄)alkanesulfonylamino, (C₁ -C₄)alkylaminoand di(C₁ -C₄)alkylamino, in which the more preferred one may be phenyl,phenyl having chloro, phenyl having methoxy, phenyl having nitro, phenylhaving amino, phenyl having acetylamino, phenyl havingmethoxycarbonylamino, phenyl having methanesulfonylamino, phenyl havingmethylamino and phenyl having dimethylamino.

Suitable "a heterocyclic group" may include the ones as exemplified for"N-containing heterocyclic group" as mentioned above,

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2sulfur atom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like, inwhich the preferred one may be unsaturated 3 to 8 memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), the morepreferred one may be pyridyl and the most preferred one may be2-pyridyl, 3-pyridyl and 4-pyridyl.

Suitable "lower alkenyl having halogen" may include 1-fluorovinyl,1-bromovinyl, 1-chloro-2-methylvinyl, 1-bromo-1-propenyl,2-chloro-2-propenyl, 1-iodo-1-butenyl, 1-bromo-2-methyl-1-propenyl,3-bromo-1,3-butadienyl, 1-chloro-1-pentenyl, 4-chloro-4-pentenyl,1-bromo-1-hexenyl and the like.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy and the like.

Suitable "halogen" may include fluoro, chloro, bromo and iodo.

Suitable "a leaving group" may include di(lower)alkylamino (e.g.dimethylamino diethylamino, N-ethylpropylamino, dibutylamino,N-pentylhexylamino, etc.), lower alkoxy as mentioned above, halogen asmentioned above, lower alkylthio (e.g. methylthio, ethylthio,propylthio, butylthio, pentylthio, hexylthio, etc.) and the like.

The processes for preparing the object compound (I) of the presentinvention are explained in detail in the following.

PROCESS 1

The object compound (Ia) or a salt thereof can be prepared by reactingthe compound (II) or a salt thereof with the compound (III) or a saltthereof.

Suitable salts of the compound (Ia), (II) and (III) can be referred toacid addition salts as exemplified for the compound (I).

This reaction is usually carried out in a conventional solvent such asalcohol (e.g. methanol, ethanol) or any other solvent which does notadversely influence the reaction.

This reaction is usually carried out under slightly acidic condition.

The reaction temperature is not critical and the reaction can be carriedout under warming to heating.

PROCESS 2

The object compound (Ic) or a salt thereof can be prepared by subjectingthe compound (Ib) or a salt thereof to dehydration reaction.

Suitable salts of the compounds (Ib) and (Ic) can be referred to acidaddition salts as exemplified for the compound (I).

The dehydration reaction of this process can be carried out according toa conventional manner and can be also carried out by reacting thecompound (Ib) or a salt thereof with lower alkyl isocyanate (e.g. methylisocyanate, etc.) in a conventional solvent (e.g. methylene chloride,chloroform, etc.) under cooling, at room temperature or under warming.

PROCESS 3

The object compound (Id) or a salt thereof can be prepared subjectingthe compound (IV) or a salt thereof to so-called Wittig type reaction.

Suitable salt of the compound (Id) can be referred to the ones asexemplified for the compound (I).

Suitable salt of the compound (IV) can be referred to acid addition saltas exemplified for the compound (I).

The reaction of this process can be carried out by reacting the compound(IV) or a salt thereof with a so-called Wittig reagent as shown in thefollowing formulae: ##STR4## [wherein R⁹ is aryl or lower alkyl, each asmentioned above,

R¹⁰ is lower alkyl as mentioned above,

R⁶ is as defined above,

A³ is lower alkylidene (e.g. methylene, ethylidene, propylidene,1-methylethylidene, butylidene, 2-methylpropylidene, pentylidene, etc.)or lower alkenylidene (e.g. vinylidene, 2-propenylidene, 2-butenylidene,4-pentenylidene, etc.), and

A⁴ is lower alkyl or lower alkenyl, each as mentioned above].

The aforesaid Wittig reagents (X) and (XI) can be prepared according toa usual manner.

The reaction of this process can be carried out in the presence of basesuch as alkali metal hydride (e.g. sodium hydride, potassium hydride,etc.), alkali metal lower alkoxide (e.g. potassium t-butoxide, etc.) orthe like in case of using Wittig reagent (XI).

The reaction is usually carried out in a conventional solvent such asdiethyl ether, tetrahydrofuran, methylene chloride, benzene, toluene,N,N-dimethylformamide or any other solvent which does not adverselyinfluence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling, at room temperature, under warming or under heating.

The reaction condition can be determined according to the kind of thecompound (IV) and the Wittig reagent to be used.

PROCESS 4

The object compound (If) or a salt thereof can be prepared by subjectingthe compound (Ie) or a salt thereof to elimination reaction of carboxyprotective group.

Suitable salts of the compounds (Ie) and (If) can be referred to theones as exemplified for the compound (I).

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic baseand an organic base such as an alkali metal [e.g. sodium, potassium,etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], thehydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g.trimethylamine, triethylamine, etc.], picoline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

PROCESS 5

The object compound (Ig) or a salt thereof can be prepared by reactingthe compound (If) or its reactive derivative at the carboxy group or asalt thereof with N-substituted amine (V) or its reactive derivative atthe amino group or a salt thereof.

Suitable salts of the compounds (If) and (Ig) can be referred to theones as exemplified for the compound (I).

Suitable salt of N-substituted amine (V) can be referred to the ones asexemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (If)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; oran activated ester [e.g. cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂ N⁺ ═CH--] ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.] or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (If) to beused.

Suitable reactive derivative at the amino group of N-substituted amine(V) may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of N-substituted amine (V) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of N-substituted amine (V) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofN-substituted amine (V) with phosphorus trichloride or phosgene, and thelike.

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (If) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine,N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

PROCESS 6

The object compound (Ii) or a salt thereof can be prepared by subjectingthe compound (Ih) or a salt thereof to halogenation reaction.

Suitable salts of the compounds (Ih) and (Ii) can be referred to theones as exemplified for the compound (I).

This halogenation reaction can be carried out according to aconventional manner, for example, by reacting the compound (Ih) or asalt thereof with halogen (e.g. bromine, chlorine, etc.) in aconventional solvent such as methylene chloride, chloroform or any othersolvent which does not adversely influence the reaction under cooling orat room temperature.

PROCESS 7

The object compound (Ij) or a salt thereof can be prepared by subjectingthe compound (Ii) or a salt thereof to elimination reaction of hydrogenhalide.

Suitable salts of the compounds (Ii) and (Ij) can be referred to theones as exemplified for the compound (I).

This elimination reaction can be carried out according to a conventionalmanner, for example, by reacting the compound (Ii) or a salt thereofwith a base such as alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, etc.), alkali metal alkoxide (e.g. sodium ethoxide,potassium t-butoxide, etc.) in a conventional solvent (e.g. chloroform,methanol, ethanol, dimethyl sulfoxide, etc.) under cooling to heating.

PROCESS 8

The object compound (Ih) or a salt thereof can be prepared by subjectingthe compound (Ij) or a salt thereof to reduction of triple bond.

The reaction of this process can be carried out according to aconventional manner to be used for reducing triple bond to double bond,for example, catalytic hydrogenation using lindler catalyst or the like.

PROCESS 9

The object compound (Ik) or a salt thereof can be prepared by subjectingthe compound (If) or its reactive derivative at the carboxy group or asalt thereof to esterification reaction.

Suitable salt of the compound (Ik) can be referred to acid addition saltas exemplified for the compound (I).

This esterification reaction can be carried out by reacting the compound(If) or its reactive derivative at the carboxy group or a salt thereofwith a conventional esterification reagent such as lower alkanol (e.g.methanol, ethanol, propanol, butanol, t-butanol, pentanol, hexanol,etc.) according to a similar manner to that of Process 5.

PROCESS 10

The object compound (Im) or a salt thereof can be prepared by subjectingthe compound (Il) or a salt thereof to lower alkylation reaction.

Suitable salts of the compounds (Il) and (Im) can be referred to acidaddition salts as exemplified for the compound (I).

The lower alkylation reaction of this process can be carried out byreacting the compound (Il) or a salt thereof with a conventional loweralkylating agent such as lower alkyl halide (e.g. methyl iodide, methylchloride, ethyl bromide, propyl iodide, isopropyl chloride, butyliodide, t-butyl chloride, pentyl bromide, hexyl iodide, etc.) or thelike in a conventional solvent (e.g. tetrahydrofuran, etc.) undercooling to warming.

PROCESS 11

The object compound (In) or a salt thereof can be prepared by subjectingthe compound (I() or a salt thereof to acylation reaction.

Suitable salt of the compound (In) can be referred to acid addition saltas exemplified for the compound (I).

The acylation reaction of this process can be carried out by reactingthe compound (I() or a salt thereof with a conventional acylating agentsuch as lower alkanoic acid (e.g. formic acid, acetic acid, propionicacid, butyric acid, isobutyric acid, pivalic acid, hexanoic acid, etc.),acid halide thereof, acid anhydride thereof or the like in aconventional solvent (e.g. pyridine, etc.) under cooling to warming.

PROCESS 12

The object compound (Ip) or a salt thereof can be prepared by subjectingthe compound (Io) or a salt thereof to elimination reaction of carboxyprotective group.

Suitable salt of the compound (Io) can be referred to acid addition saltas exemplified for the compound (I).

Suitable salt of the compound (Ip) can be referred to the ones asexemplified for the compound (I).

The elimination reaction of this process can be carried out according toa similar manner to that of Process 4.

PROCESS 13

The object compound (Ir) or a salt thereof can be prepared by subjectingthe compound (Iq) or a salt thereof to reduction of nitro group.

Suitable salts of the compounds (Iq) and (Ir) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out according to a conventional manner tobe used for reducing nitro group to amino group, for example, by usingcombination of metal or its salt (e.g. tin, stannous chloride, iron,ferrous chloride, ferrous sulfate, zinc, etc.) and acid (e.g.hydrochloric acid, sulfuric acid, acetic acid, etc.).

PROCESS 14

The object compound (Is) or a salt thereof can be prepared by subjectingthe compound (Ir) or a salt thereof to introduction reaction of aminoprotective group.

Suitable salts of the compounds (Ir) and (Is) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out by reacting the compound (Ir) or a saltthereof with a conventional agent for introducing amino protective groupsuch as lower alkanoic acid, acid halide thereof and acid anhydridethereof as mentioned before; lower alkyl haloformate (e.g. methylchloroformate, ethyl chloroformate, propyl bromoformate, isopropylchloroformate, butyl bromoformate, t-butyl chloroformate, pentylchloroformate, hexyl chloroformate, etc.); lower alkanesulfonyl halide(e.g. methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonylbromide, isopropanesulfonyl chloride, butanesulfonyl bromide,t-butanesulfonyl chloride, pentanesulfonyl chloride, hexanesulfonylchloride, etc.); lower alkyl halide as mentioned before; or the like ina conventional solvent (e.g. methylene chloride, toluene,N,N-dimethylformamide, etc.) under cooling to heating.

PROCESS 15

The object compound (Id) or a salt thereof can be prepared by reactingthe compound (VI) or a salt thereof with the compound (VII) or a saltthereof.

Suitable salts of the compound (VII) can be referred to the ones asexemplified for the compound (I).

Suitable salt of the compound (VI) can be referred to acid addition saltas exemplified for the compound (I).

This reaction is preferably carried out in the presence of acid such asLewis acid [e.g. aluminum halide (e.g. aluminum chloride, etc.), boronhalide (e.g. boron trifluoride, etc.)], inorganic acid (e.g.hydrochloric acid, sulfuric acid, etc.), organic acid (e.g. acetic acid,etc.) or the like.

This reaction is usually carried out in a conventional solvent such asmethylene chloride, chloroform, tetrahydrofuran, N,N-dimethylformamideor any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and this reaction can becarried out under cooling, at room temperature or under warming toheating.

PROCESS 16

The object compound (It) or a salt thereof can be prepared by reactingthe compound (VIII) or its reactive derivative at the carboxy group or asalt thereof with N-substituted amine (V) or its reactive derivative atthe amino group or a salt thereof.

Suitable salts of the compounds (It) and (VIII) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out according to a similar manner to thatof Process 5.

PROCESS 17

The object compound (Iu) or a salt thereof can be prepared by subjectingthe compound (IX) or a salt thereof to reduction of nitroso group.

Suitable salts of the compounds (Iu) and (IX) can be referred to acidaddition salts as exemplified for the compound (I).

The reduction of this process can be carried out according to aconventional manner to be used for reducing nitroso group to aminogroup. Said method can be referred to the ones as exemplified forreducing method of nitro group in Process 13.

In case that an organic acid such as lower alkanoic acid is used as anacid, the resultant amino group sometimes further reacts with said acidto give a corresponding protected amino group. This case is alsoincluded within the scope of the present invention.

PROCESS 18

The object compound (Iw) or a salt thereof can be prepared by subjectingthe compound (Iv) or a salt thereof to introduction reaction of aminoprotective group.

Suitable salts of the compounds (Iv) and (Iw) can be referred to acidaddition salts as exemplified for the compound (I).

This reaction can be carried out according to a similar manner to thatof Process 14.

It is to be noted the object compound (I) may include one or morestereoisomers due to asymmetric carbon atom(s) and double bond, and allof such isomers and a mixture thereof are included within the scope ofthe present invention.

It is further to be noted isomerization or rearrangement of the objectcompound (I) may occur due to the effect of the light, acid, base or thelike, and the compound obtained as the result of said isomerization orrearrangement is also included within the scope of the presentinvention.

The object compound (I) and a salt thereof of the present inventionpossess the vasodilative activity and the activity of increasing therenal blood flow, and so are useful for diuretic, antihypertensive agentand remedy for renal insufficiency; also possess the inhibiting activityof platelet aggregation and so are useful for remedy for thrombosis; andfurther possess the cardiotonic activity and so are useful forcardiotonic agent.

The object compound (I) or a salt thereof of the present invention canbe used for the treatment of edema, hypertension, renal insufficiency,thrombosis and congestive heart failure by administering it to human oranimals.

In order to show this usefulness of the compound (I) of the presentinvention, the several pharmacological test results of therepresentative compound of the present invention are shown in thefollowing.

TEST 1. VASODILATIVE ACTIVITY [I] Test Method

Male S.D. strain rats, weighing 200-300 g, were killed by bleeding andthe thoracic aorta were removed. The helical strips (2.0×15 mm) weresuspended in an organ bath filled with 25 ml of Tyrode's solution. Thestrips were connected to an strain gauge and the tension was measuredisometrically. The bath solution was bubbled with a mixture of 95% O₂and 5% CO₂ and was maintained at 37° C. After the resting tension wasadjusted to 0.5 g, the arterial strips were contracted by 3.2×10⁻⁸ Mnorepinephrine.

The test drug was added in the organ bath cumulatively. At the end ofeach test, 10⁻⁴ M of papaverine was added to the organ bath to obtainthe maximum relaxation.

[II] Test Compound

(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer) (The compound of Example 22)

[III] Test Result

IC₅₀ value=5.3×10⁻⁷ (g/ml)

TEST 2. ACTIVITY OF INCREASING THE RENAL BLOOD FLOW [I] Test Method

Adult Beagle dogs of either sex, weighing 8-15 kg, were used. Underanesthesia with pentobarbital sodium (35 mg/kg i.p.), the trachea wasintubated for artificial respiration. Catheters were placed in anfemoral vein for drug administration.

A short segment of left renal artery was exposed by a flank incision andcleared of adhering tissue to accommodate positioning of anelectromagnetic flow probe. Renal blood flow was measured by connectingthe flow probe to an flowmeter.

[II] Test Compound

The same compound that was used in Test 1.

    ______________________________________                                        [III] Test Result                                                                            Increasing % of                                                Dose (mg/kg)   Renal Blood Flow                                               ______________________________________                                        0.1            +19.7                                                          ______________________________________                                    

TEST 3. DIURETIC ACTIVITY [I] Test Method

Male JCL:SD strain rats aged 6 weeks and weighing 170-206 g were usedafter starving for 18 hours. Immediately after oral dosing with the testdrug suspended in 0.5% methylcellulose (0.5% MC), the animals were given20 ml/kg physiological saline orally. The rats were housed by threes ina metabolism cage. The urine was collected for 3 hours. Urine volume wasmeasured with a volumetric cylinder; and urinary uric acid, with aDeterminer UA kit^(R) (Kyowa Medex Co., Ltd.). The tests were conductedin 3 groups of 3 animals each.

[II] Test Compound

The same compound that was used in Test 1.

    ______________________________________                                        [III] Test Results                                                            Excretion of Urine and Uric Acid                                              (control = 100%)                                                                           Excretion of                                                                             Excretion of Uric                                     Dose (mg/kg) Urine (%)  Acid (%)                                              ______________________________________                                        10           344        125                                                   ______________________________________                                    

TEST 4. ANTIHYPERTENSIVE ACTIVITY [I] Test Method

Eleven-week old male Wistar rats were uninephrectomized underanesthesia. Deoxycorticosterone acetate (DOCA), suspended in peanut oil,was injected 30 mg/kg subcutaneously twice a week and 1% saline wassubstituted for the drinking water.

Animals with mean blood pressure 150-200 mmHg were used for experimentbetween 5 and 13 weeks after surgery.

Test Compound (Dosage: 10 mg/kg) was administered orally to DOCAhypertensive rats daily for 5 days.

Blood pressure was measured at femoral artery by means of a pressuretransducer and recorded as electrically integrated values of meanarterial pressure.

[II] Test Compound

The same compound that was used in Test 1.

[III] Test Result

Maximum Decrease of Blood Pressure (%)=27

TEST 5. INHIBITING ACTIVITY OF PLATELET AGGREGATION [I] Test Method

Blood was collected from the carotid artery of male Japanese Whiterabbits weighing 2.5-3.0 kg, and was mixed with 1/10 volume of 3.8%sodium citrate. Platelet rich plasma (PRP) was obtained aftercentrifuging the mixture at 150×g for 15 min. Platelet aggregation wasmeasured with an aggregometer (Nikohkizai, NKK HEMA TRACER, ModelPAT-4A). 0.24 ml of PRP containing 6.5-7.5×10⁸ platelet/ml and 5 μl oftest solution or PEG200: EtOH: H₂ O (1:1:2) were successively added tothe cuvette. The mixture was stirred for 2 min at 37° C. and 5 μl of 125μg/ml collagen was added to induce aggregation. The test was conductedusing PRP obtained from 3 different rabbits.

[II] Test Compound

The same compound that was used in Test 1.

[III] Test Result

Inhibiting Activity of Platelet Aggregation

IC₅₀ value=7.9×10⁻⁶ (g/ml)

TEST 6. CARDIOTONIC ACTIVITY [I] Test Method

Male Hartley strain guinea-pigs, weighing 500-600 g, were killed bybleeding and the heart was removed. An atrial strip was removed andsuspended in an organ bath containing 50 ml of Tyrode's solutionmaintained at 30° C. and aerated with a gas mixture of 95% O₂ - 5% CO₂.The atrium was connected to a strain gauge under an initial tension of0.4-0.6 g. After constant motility had been obtained the drug was addedto the bath solution and the effect on the contractile force and beatingrate were observed for 30 min. The effect was expressed as percentagevalues before and after dosing. 3 separate preparations were used foreach concentration.

[II] Test Compound

The same compound that was used in Test 1.

    ______________________________________                                        [III] Test Results                                                                            Increasing % of                                                                           Increasing %                                      Concentration of                                                                              Contractile of Heart                                          Test compound (g/ml)                                                                          force       Rate                                              ______________________________________                                        10.sup.-6       10.0        -10.7                                             ______________________________________                                    

TEST 7. ANTIHYPERTENSIVE ACTIVITY [I] Test Method

Eleven-week old male Wistar rats were uninephrectomized underanesthesia. Deoxycorticosterone acetate (DOCA), suspended in peanut oil,was injected 30 mg/kg subcutaneously twice a week and 1% saline wassubstituted for the drinking water.

Animals with mean blood pressure 150-200 mmHg were used for experimentbetween 5 and 13 weeks after surgery.

Test Compound (Dosage: 3.2 mg/kg) was administered orally to DOCAhypertensive rats daily for 5 days.

Blood pressure was measured at femoral artery by means of a pressuretransducer and recorded as electrically integrated values of meanarterial pressure.

[II] Test Compound

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine .1/2 fumalate (trans isomer) (the compound of Example 9)

    ______________________________________                                        [III] Test Result                                                             Maximum Decrease of                                                           Blood Pressure (%)                                                            ______________________________________                                        32                                                                            ______________________________________                                    

For therapeutic administration, the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration.

The pharmaceutical preparations may be in solid form such as tablet,granule, powder, capsule, or liquid form such as solution, suspension,syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, citric acid, tartaric acid, stearic acid,magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin,agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, andthe like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases, a kind of thecompound (I) to be applied, etc. In general, amount between 1 mg andabout 1,000 mg or even more per day may be administered to a patient. Anaverage single dose of about 1 mg, 5 mg, 10 mg, 20 mg of the objectcompound (I) of the present invention may be used as diuretic,antihypertensive agent, remedy for renal insufficiency, remedy forthrombosis or cardiotonic agent.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

EXAMPLE 1 ##STR5##

A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) andsemicarbazide hydrochloride (0.25 g) in ethanol (7 ml) was refluxed for1 hour and then cooled. The resulting precipitates were filtered andrecrystallized from a mixture of water and ethanol to give2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde semicarbazone (0.26 g).

mp: 221°-222° C.

IR (Nujol): 3350, 1660, 1570 cm⁻¹

NMR (DMSO-d₆, δ): 6.33 (2H, s), 7.00-7.90 (7H, m), 8.27 (1H, s), 8.43(1H, dd, J=1.0, 8.0 Hz), 8.85 (1H, d, J=6.5 Hz), 9.97 (1H, s)

MS: 279 (M⁺)

EXAMPLE 2 ##STR6##

A mixture of [2-(dimethylamino)aceto]hydrazide dihydrochloride (624 mg)and potassium carbonate (910 mg) in ethanol (7 ml) was heated at 60° C.To the mixture 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (666 mg)was added and refluxed for 2.5 hours. After being cooled, the mixturewas filtered off and the filtrate was evaporated in vacuo. The residuewas chromatographed on silica gel (20 g) with a mixture of chloroformand methanol (20:1) as an eluent. The fractions containing the objectcompound were combined and evaporated in vacuo. The residue wasrecrystallized from ethanol to give2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde [2-(dimethylamino)acetyl]hydrazone as crystals (0.63 g).

mp: 172°-173° C.

IR (Nujol): 1670, 1620 cm⁻¹

NMR (CDCl₃ δ): 2.33 (3H, s), 3.13 (2H, s), 6.95 (1H, dt, J=2.0, 7.0 Hz),7.30-7.83 (7H, m), 8.37 (1H, s), 8.53 (1H, dd, J=1.0, 7.5 Hz), 9.83-10.0(1H, m)

MS: 321 (M⁺)

Analysis Calcd. for C₁₈ H₁₉ N₅ O; C:67.27H:5.96N:21.79; FoundC:67.65H:5.96N:21.80.

EXAMPLE 3 ##STR7##

2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(2-ethylpiperidino)acetyl]hydrazone was obtained according to asimilar manner to that of Example 2.

mp: 156°-157.5° C.

IR (Nujol): 3200, 1660, 1625, 1595, 1520 cm⁻¹

NMR (CDCl₃ δ): 0.90 (3H, t, J=7.0 Hz), 1.13-2.00 (8H, m), 2.20-2.67 (2H,m), 2.77-3.10 (1H, m), 3.07 (1H, d, J=17.0 Hz), 3.50 (1H, d, J=17.0 Hz),7.02 (1H, t, J=7.0 Hz), 7.30-7.90 (6H, m), 8.43-8.73 (3H, m), 10.10 (1H,broad s)

MS: 389 (M⁺)

Analysis Calcd. for C₂₃ H₂₇ N₅ O: C:70.93H:6.99N:17.98; FoundC:70.88H:6.93N:17.98.

EXAMPLE 4 ##STR8##

A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) andhydroxylamine hydrochloride (0.17 g) in ethanol (5 ml) was refluxed for1.5 hours and evaporated in vacuo. The residue was triturated with ethylacetate and recrystallized from a mixture of ethanol and ethyl acetateto give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oximehydrochloride (0.28 g).

mp: 156°-157° C.

IR (Nujol): 2380, 1620 cm⁻¹

NMR (DMSO-d₆ δ): 7.07-8.17 (9H, m), 8.80 (1H, d, J=8 Hz), 10.33 (1H, s)

MS: 237 (M⁺)

EXAMPLE 5 ##STR9##

A solution of methyl isocyanate (0.19 g) in methylene chloride (2ml) wasadded dropwise to a mixture of2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (0.52 g) inchloroform (4 ml) with stirring and ice-cooling. The mixture was stirredat room temperature for 2 hours and allowed to stand at room temperatureovernight. The solvent was evaporated in vacuo and the residue waschromatographed on silica gel (20 g) with methylene chloride as aneluent. The fractions containing the object compound were combined (20ml) and evaporated in vacuo. The residue was recrystallized from ethylacetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.21 g).

mp: 138°-139° C.

IR (Nujol): 2220, 1620 cm⁻¹

NMR (CDCl₃ δ): 7.03 (1H, dt, J=2.0, 7.0 Hz), 7.43-7.93 (5H, m),8.03-8.37 (2H, m), 8.58 (1H, dd, J=1.0, 7.0 Hz)

MS: 219 (M⁺)

EXAMPLE 6 ##STR10##

A mixture of 2-phenylpyrazolo[1,5-a]-pyridine-3-carbaldehyde (0.50 g)and acetonylidenetriphenylphosphorane ##STR11## (0.82 g) in benzene (6ml) was refluxed for 4 hours and then the solvent was evaporated invacuo. The residue was chromatographed on silica gel (20 g) withchloroform as an eluent. The fractions containing the object compound,were combined and evaporated in vacuo. The residue was recrystallizedfrom ethanol to give crystals of4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3-buten-2-one (trans isomer)(0.21 g).

mp: 134.5°-135.5° C.

IR (Nujol): 1650, 1600, 1500 cm⁻¹

NMR (CDCl₃ δ): 2.37 (3H, s), 6.67 (1H, d, J=16.0 Hz), 7.00 (1H, dt,J=2.0, 6.0 Hz), 7.10-8.07 (9H, m), 8.63 (1H, d, J=6.0 Hz)

MS: 262 (M⁺)

Analysis Calcd for C₁₇ H₁₄ N₂ O; C:77.84H:5.38N:10.68; FoundC:78.55H:5.40N:10.65.

EXAMPLE 7 ##STR12##

A solution of trimethyl phosphonoacetate (4.0 g) in toluene (10 ml) wasadded to a mixture of sodium hydride (63%, 880 mg) in toluene (45 ml)with stirring and cooling and then heated at 60° C. for 20 minutes. Tothe mixture 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (2.0 g) wasadded and heated at 60° C. for 8 hours. A saturated sodium bicarbonatesolution (30 ml) was added to the reaction mixture and extracted withethyl acetate (30 ml, 2 times). The extract was washed with brine (30ml), dried over magnesium sulfate and evaporated in vacuo. The residuewas recrystallized from a mixture of ethyl acetate and isopropyl alcoholto give crystals of methyl3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (1.34 g).

mp: 139°-139.5° C.

IR (Nujol): 1700, 1610 cm⁻¹

NMR (CDCl₃ δ): 3.77 (3H, s), 6.28 (1H, d, J=16 Hz), 6.88 (1H, dt, J=1.5,6.0 Hz), 7.20-7.90 (7H, m), 7.92 (1H, d, J=16 Hz), 8.50 (1H, d, J=6.0Hz)

MS: 278 (M⁺)

EXAMPLE 8 ##STR13##

A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate(trans isomer) (4.05 g) in 1N sodium hydroxide solution (58.3 ml) andmethanol (80 ml) was refluxed for 1 hour and evaporated in vacuo. Theresidue was dissolved in water and washed with chloroform. The aqueouslayer was acidified with 1N hydrochloric acid. The resultingprecipitates were filtered and recrystallized from isopropyl alcohol togive crystals of 3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acrylic acid(2.65 g).

mp: 225°-225° C.

IR (Nujol): 1660, 1590 cm⁻¹

NMR (DMSO-d₆ δ): 6.32 (1H, d, J=16.0 Hz), 7.15 (1H, dt, J=1.0, 6.0 Hz),7.40-7.92 (7H, m), 8.10 (1H, d, J=7.0 Hz), 8.87 (1H, d, J=6.0 Hz)

MS: 264 (M⁺)

Analysis Calcd for C₁₆ H₁₂ N₂ O₂ : C:72.72H:4.58N:10.60; FoundC:73.13H;4.50N:10.67.

EXAMPLE 9 ##STR14##

Isobutyl chloroformate (1.04 g) was added dropwise to a mixture of3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) (2.0g) and triethylamine (0.766 g) in methylene chloride (40 ml) andtetrahydrofuran (10 ml) at -20° C. with stirring. After being stirred atthe same temperature for 30 minutes, a solution of 2-ethylpiperidine(0.942 g) in tetrahydrofuran (10 ml) was added thereto dropwise at -20°C. and the mixture was stirred at -20° C. to 10° C. for 2 hours. Themixture was warmed to room temperature and evaporated in vacuo. Asaturated sodium bicarbonate solution was added to the residue andextracted twice with chloroform (50 ml). The combined extract was washedwith saturated brine (50 ml), dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on silica gel (40g) with chloroform as an eluent. The fractions containing the objectcompound were combined and evaporated in vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer) (1.30 g) as an oil.

This compound was converted to 1/2fumalate in a usual manner. Thecrystals were recrystallized from a mixture of n-hexane and diethylether to give yellow crystals of1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloy]-2-ethylpiperidine.1/2fumalate(trans isomer) (0.96 g).

mp: 121°-122° C.

IR (Nujol): 1705, 1635, 1580) 1540, 1510 cm⁻¹

NMR (DMSO-d₆ δ): 0.77 (3H, t, J=7.0 Hz), 1.30-1.83 (8H, m), 6.66 (1H,s), 6.83 (1H, d, J=16.0 Hz), 7.00-7.83 (8H, m), 8.07 (1H, d, J=9.0 Hz),8.77 (1H, d, J=7.0 Hz)

Analysis Calcd for C₂₃ H₂₅ N₃ O.1/2C₄ H₄ O₄ : C:71.92H:6.52N:10.06;Found C:72.01H:6.60N:10.03.

The following compounds (Examples 10 to 17) were obtained according to asimilar manner to that of Example 9.

EXAMPLE 10 ##STR15##

1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]pyrrolidine (transisomer)

mp: 190°-191° C.

IR (Nujol): 1640, 1590 cm⁻¹

NMR (CDCl₃ δ): 1.70-2.30 (4H, m), 3.33-3.90 (4H, m), 6.53 (1H, d, J=16.0Hz), 6.77-8.13 (8H, m), 8.57 (1H, d, J=7.0 Hz)

Analysis Calcd for C₂₀ H₁₉ N₃ O: C:75.69H:6.03N:13.24; FoundC:76.08H:5.95N:13.16.

MS: 317 (M⁺)

EXAMPLE 11 ##STR16##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine (transisomer)

mp: 111.5°-112° C.

IR (Nujol): 1630, 1580 cm⁻¹

NMR (CDCl₃, δ): 1.40-1.75 (6H, m), 3.30-3.70 (4H, broad s), 6.65 (1H, d,J=15.0 Hz), 6.83. (1H, dt, J=2.0, 6.0 Hz), 7.13-7.80 (7H, m), 7.83 (1H,d, J=15.0 Hz), 8.45 (1H, d, J=6.0 Hz)

Analysis Calcd for C₂₁ H₂₁ N₃ O: C:76.11, H:6.39, N:12.68; FoundC:76.08, H:6.32, N:12 65.

MS: 331 (M⁺)

EXAMPLE 12 ##STR17##

4-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]morpholine (transisomer)

mp: 154.5°-155.5° C.

IR (Nujol): 1625, 1580 cm⁻¹

NMR (CDCl₃, δ): 3.63.(8H, broad s), 6.60 (1H, d, J=16.0 Hz), 6.90 (1H,dt, J=2.0, 7.0 Hz), 7.15-7.83 (7H, m), 8.00 (1H, d, J=16.0 Hz), 8.50(1H, dd, J=1.0, 7.0 Hz)

MS: 333 (M⁺)

Analysis Calcd for C₂₀ H₁₉ N₃ O₂ : C:72.05, H:5.74, N:12.60; FoundC:72.55, H:5.72, N:12.58.

EXAMPLE 13 ##STR18##

1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-methylpiperazinehydrochloride (trans isomer)

mp: 261°-262° C.

IR (Nujol): 2400, 1650, 1580, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 2.78 (3H, s), 3.00-3.70 (8H, m), 6.99 (1H, d, J=11Hz), 7.00-7.83 (7H, m), 7.76 (1H, d, J=l1Hz), 8.27 (1H, d, J=6.0 Hz),8.90 (1H, d, J=5.0 Hz)

Analysis Calcd for C₂₁ H₂₂ N₄ O HCl: C:65.88, H:6.05, N:14.6; Found C:6590, H:6.01, N:14.66.

EXAMPLE 14 ##STR19##

N-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

mp: 208°-209° C.

IR (Nujol): 3275, 1640, 1605 cm⁻¹

NMR (DMSO-d₆, δ): 2.73 (3H, d, J=5.0 Hz), 6.77 (1H, d, J=16.0 Hz),7.0-8.10 (9H, m), 8.90 (1H, d, J=6.0 Hz)

MS: 277 (M⁺)

EXAMPLE 15 ##STR20##

N-Isopropyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

mp: 210°-210.5° C.

IR (Nujol): 3275, 1640, 1600 cm⁻¹

NMR (CDCl₃, δ): 1.22 (3H, d, J=7.0 Hz), 6.23 (1H, d, J=16.0 Hz), 6.90(1H, dt, J=2.0, 7.0 Hz), 7.20-8.07 (8H, m), 8.53 (1H, dd, J=2.0, 7.0 Hz)

Analysis Calcd for C₁₉ H₁₉ N₃ O: C:74.73, H:.6 27, N:13.76; FoundC:74.96, H:6.16, N:13.80.

MS: 305 (M⁺)

EXAMPLE 16 ##STR21##

N,N-Dimethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

mp: 154°-155° C.

IR (Nujol): 1640, 1590 cm⁻¹

NMR: (CDCl₃, δ): 3.05 (6H, s), 6.70 (1H, d, J=16.0 Hz), 6.87 (1H, dt,J=2.0, 7.0 Hz), 7.15-7 78 (7H, m), 7.95 (1H, d, J=16.0 Hz), 8.50 (1H,dd, J=1.0, 7.0 Hz)

Analysis Calcd for C₁₈ H₁₇ N₃ O: C:74.21, H:5.88, N:14.42; FoundC:74.44, H:5.86, N:14.42.

MS: 291 (M⁺)

EXAMPLE 17 ##STR22##

N-(Tricyclo[3.3.1.1³,7]decan-1-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

mp: 232.5°-233.5° C.

IR (Nujol): 3280, 1650, 1590, 1535, 1500 cm⁻¹

NMR (CDCl₃, δ): 1.53-1.83 (6H, m), 1.90-2.27 (9H, m), 5.23 (1H, broads), 6.22 (1H, d, J=16.0 Hz), 6.90 (1H, dt, J=1.0, 7.0 Hz), 7.30 (1H, t,J=6.0 Hz), 7.43-7.97 (7H, m), 8.57 (1H, d, J=6.0 Hz)

Analysis Calcd for C₂₆ H₂₇ N₃ O: C:78.56, H:6.85, N:10.57; FoundC:77.85, H:7.01, N:10.30.

MS: 397 (M⁺)

EXAMPLE 18 ##STR23##

Isobutyl chloroformate (2.07 g) was added dropwise to a mixture of3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acrylic acid (trans isomer)(4.0g) and triethylamine (1.53 g) in N,N-dimethylformamide (40 ml) at -20°C. with stirring. After being stirred at the same temperature for 30minutes, a solution of (2R)-2-ethylpiperidine (1.88 g) inN,N-dimethylformamide (20 ml) was added dropwise at -20° C. and themixture was stirred at -20° C. to -10° C. for 2 hours.

The reaction mixture was poured into water (100 ml) and extracted twicewith ethyl acetate (50 ml). The combined extracts were washed withsaturated sodium chloride aqueous solution (30 ml), dried over magnesiumsulfate and evaporated in vacuo.

The residue was chromatographed on silica gel (80 g) with chloroform asan eluent. The fractions containing the object compound were combinedand evaporated in vacuo to give(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)(3.13 g) as an oil.

[α]_(D) ²⁶ =-34.30° (c=1.0, EtOH)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

NMR (CDCl₃, δ): 0.85 (3H, t, J=7.0 Hz), 1.43-1.90 (6H, m), 2.50-3.20(1H, m), 3.83-4.73 (2H, m), 6.70 (1H, d, J=16.0 Hz), 6.88 (1H, dt, J=1.5Hz and 7.0 Hz), 7.17-7.93 (7H, m), 7.97 (1H, d, J=16.0 Hz), 8.54 (1H,dd, J=1.0 Hz and 7.0 Hz)

MS: 359 (M⁺)

EXAMPLE 19 ##STR24##

(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)(1.79 g) was converted to hydrobromic acid salt in a usualmanner. The crystals were recrystallized from a mixture of ethyl acetateand acetone to give yellow crystals of(2R)-1-[3(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2ethylpiperidinehydrobromide (trans isomer)(1.48 g).

mp: 103°-104° C.

IR (Nujol): 1630, 1600, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 0.78 (3H, t, J=7 Hz), 1.18-1.87 (6H, m), 2.70-3.23(1H, m), 4.00-3.67 (2H, m), 6.91 (1H, d, J=15.0 Hz), 7.12 (1H, dt, J=2.0Hz and 7.0 Hz), 7.33-8.26 (10H, m), 8.42 (1H, s), 8.83 (1H, d, J=7.0 Hz)

[α]_(D) ²⁶.4 =-29.39° (c=0.966; EtOH)

EXAMPLE 20 ##STR25##

Isobutyl chloroformate (2.07 g) was added dropwise to a mixture of3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer)(4.0g) and triethylamine (1.53 g) in N,N-dimethylformamide (40 ml) at -20°C. with stirring. After being stirred at the same temperature for 30minutes, a solution of (2S)-2-ethylpiperidine (1.88 g) inN,N-dimethylformamide (20 ml) was added dropwise at -20° C. and themixture was stirred at -20° C. to -10° C. for 2 hurs.

The reaction mixture was poured into water (100 ml) and extracted twicewith ethyl acetate (50 ml). The combined extracts were washed withsaturated sodium chloride aqueous solution (30 ml), dried over magnesiumsulfate and evaporated in vacuo.

The residue was chromatographed on silica gel (80 g) with chloroform asan eluent. The fractions containing the object compound were combinedand evaporated in vacuo to give(2S)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer) as an oil.

[α]_(D) ²⁶ =+34.80° (c=1.0; EtOH)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

NMR (CDCl₃, δ): 0.85 (3H, t, J=7.0 Hz), 1.43-1.90 (6H, m), 2.50-3.20(1H, m), 3.83-4.73 (2H, m), 6.70 (1H, d, J=16.0 Hz), 6.88 (1H, dt, J=1.5Hz and 7.0 Hz), 7.17-7.93 (7H, m), 7.97 (1H, d, J=16.0 Hz), 8.54 (1H,dd, J=1.0 Hz and 7.0 Hz)

MS 359 (M⁺)

EXAMPLE 21 ##STR26##

(2S)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)(2.11 g) was converted to hydrobromic acid salt in a usualmanner. The crystals were recrystallized from a mixture of ethyl acetateand acetone to give yellow crystals of(2S)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidinehydrobromide (trans isomer)(1.75 g).

mp: 104°-105° C.

IR (Nujol): 1630, 1600, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 0.78 (3H, t, J=7.0 Hz), 1.18-1.87 (6H, m), 2.70-3.23(1H, m), 4.00-3.67 (2H, m), 6.88 (1H, d, J=16.0 Hz), 7.11 (1H, dt, J=2.0Hz and 7.0 Hz), 7.36-8.28 (10H, m), 8.77 (1H, s), 8.83 (1H, d, J=7.0 Hz)

[α]_(D) ²⁶.4 =+29.91° (c=0.926; EtOH)

EXAMPLE 22 ##STR27##

Thionyl chloride (1.79g) was added dropwise to a stirred mixture of3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) (2.00g) and N,N-dimethylformamide (4 drops) in methylene chloride (10 ml)under ice-cooling.

After being stirred at room temperature for 3 hours, the solvent wasevaporated in vacuo to give acid chloride derivative.

On the other hand, (R)-2-(2-hydroxyethyl)piperidine (6.48 g) was addeddropwise to bis-(trimethylsilyl)acetamide (6.80 g) under ice-cooling.The mixture was warmed to room temperature with stirring for 20 minutes.

Triethylamine (1.53 g) and methylene chloride (40 ml) was added to themixture. The above acid chloride derivative was added to this mixtureunder ice-cooling, and stirred at room temperature for 1 hour. Thesolvent was evaporated in vacuo and a mixture of 1N hydrochloric acidsolution (10 ml) and ethyl acetate (10 ml) was added thereto.

After the resultant mixture was stirred for 30 minutes, 1N sodiumhydroxide solution (12 ml) was added to the mixture and extracted withmethylene chloride (60 ml). The extract was dried over magnesium sulfateand the solvent was evaporated in vacuo. The residue was chromatographedon silica gel (40 g) with a mixture of methylene chloride and ethylacetate (5:1) as an eluent. The fractions containing the object compoundwere combined and evaporated in vacuo to give(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer) (1.83 g).

mp: 145°-146.5° C.

[α]_(D) ²⁴.0 =+39.61° (C=1.04, 95% EtOH)

IR(Nujol): 3350, 1640, 1575, 1520 cm⁻¹

NMR(CDCl₃, δ): 1.23˜2.20(8H, m), 2.63˜3.90(4H, m), 400˜4.40(1H, m),4.67˜5.10(1H, m), 6.63(1H, d, J=16.0 Hz), 8.50(1H, t, J=7.0 Hz),7.77(7H, m), 7.92(1H, d, J=16.0 Hz), 8.47(1H, d, J=7.0 Hz)

Analysis Calcd for C₂₃ H₂₅ N₃ O₂ : C 73.58, H 6.71, N 11.19; Found C73.98, H 6.76, N 11.24.

MS: 375 (M⁺)

The following compounds (Examples 23 and 24) were obtained according toa similar manner to that of Example 22.

EXAMPLE 23 ##STR28##

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

mp: 98°˜99.5° C.

[α]_(D) ²³.0 =-41.20° (C=1.0, 95% EtOH)

IR(CHCl₃) 3330, 1635, 1570, 1520 cm⁻¹

NMR(CDCl₃, δ): 1.17˜2.20(8H, m), 2.67˜4.00(4H, m), 2.78(1H, s),4.67˜5.10(1H, m), 6.70(1H, d, J=16.0 Hz), 6.89(1H, t, J=7.0 Hz),7.25˜7.87(7H, m), 8.00(1H, d, J=16.0 Hz), 8.57(1H, d, J=7.0 Hz)

Analysis Calcd for C₂₃ H₂₅ N₃ O₂ : C 73.58, H 6.71, N 11.19; Found C73.68, H 6.81, N 11.21.

MS: 375 (M⁺)

EXAMPLE 24 ##STR29##

(2RS)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

mp: 140.5°-141.5° C.

IR(Nujol): 3280, 1625, 1560, 1510 cm⁻¹

NMR(CDCl₃, δ): 1.17˜2.20(8H, m), 2.54˜3.90(5H, m), 4.67˜5.10(1H, m),6.64(1H, d, J=16.5 Hz), 6.85(1H, dt, J=7.0 Hz and 1.0 Hz, 7.15˜7.77(7H,m), 7.92(1H, d, J=16.5 Hz), 8.47(1H, d, J=7.0 Hz)

Analysis Calcd for C₂₃ H₂₅ N₃ O₂ : C 73.58, H 6.71, N 11.19; Found C73.50, H 6.56, N 11.14.

MS: 375 (M⁺)

PREPARATION 1 ##STR30##

2-Phenylpyrazolo[1,5-a]pyridine (2.00 g) was added to a stirred solutionof acetic anhydride (4.20 g) and two drops of sulfuric acid at roomtemperature. After being stirred under reflux for 14 hours, the reactionmixture was poured onto 80 ml of 4N NaOH aqueous solution and extractedwith chloroform (30 ml×2). The extracts were combined and washed withwater (30 ml), saturated sodium chloride aqueous solution (30 ml), thendried over magnesium sulfate and evaporated in vacuo. The residualcrystals were recrystallized from diisopropyl ether to give2-phenyl-3-acetylpyrazolo[1,5-a]pyridine (1.16 g).

mp: 84° to 85° C.

IR (Nujol): 1640, 1620, 1495 cm⁻¹

NMR (CDCl₃, δ): 2.23 (3H, s), 7.04 (1H, td, J=7 Hz and 1Hz), 7.40-7.70(6H, m), 8.51 (2H, t, 7 Hz)

Analysis Calcd. for C₁₅ H₁₂ N₂ O: C 76.25, H 5.12, N 11.86; Found: C77.25, H 5.21, N 11.87.

MS: 236 (M⁺)

PREPARATION 2 ##STR31##

A solution of sodium nitrite (533 mg) in water (2.5 ml) was addeddropwise to a solution of 2-phenylpyrazolo[1,5-a]pyridine (1.0 g) inacetic acid (5 ml) at 13° to 15° C. After being stirred at the sametemperature for 20 minutes, the reaction mixture was poured ontoice-water. Resultant precipitates were collected by filtration, washedwith water and recrystallized from acetone to give crystals of3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.82 g).

mp: 161° to 163° C.

IR (Nujol): 1620 cm⁻¹

NMR (CDCl₃, δ): 7.28 (1H, td, J=6.5 Hz and 2.0 Hz), 7.17-8.02 (5H, m),8.27-8.77 (3H, m)

Analysis Calcd. for C₁₃ H₉ N₃ O: C 69.94, H 4.06, N 18.83; Found: C70.26, H 4.18, N 18.97.

MS: 223 (M⁺)

EXAMPLE 25 ##STR32##

Aluminum chloride (298 mg) was added portionwise to a solution of2-phenylpyrazolo[1,5-a]pyridine (145 mg) and ethyl3-dimethylaminoacrylate (316 mg) in methylene chloride (2 ml) at 5° to6° C. After being stirred at room temperature overnight, the reactionmixture was poured onto water (50 ml), neutralized with saturatedaqueous sodium bicarbonate solution, and extracted with chloroform (50ml×2). The extracts were washed with saturated sodium chloride aqueoussolution (20 ml), dried over magnesium sulfate, and evaporated in vacuo.The residue was chromatographed on silica gel with a mixture ofchloroform and n-hexane (1:1) as an eluent. The fractions containing theobjective compound were combined and evaporated in vacuo to give ethyl3-(2-phenylpyrazolo[1,5-a]pyridin -3-yl)acrylate (trans isomer) (189.4mg).

IR (Nujol): 1690, 1615, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.30 (3H, t, J=6.0 Hz), 4.27 (2H, q, J=6.0 Hz), 6.30(1H, d, J=16.0 Hz), 6.88 (1H, td, J=6.0 Hz and 2.0 Hz), 7.16-8.33 (8H,m), 8.53 (1H, dd, J=8.0 Hz and 1.0 Hz)

EXAMPLE 26 ##STR33##

A mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.81 g) and zincpowder (0.95 g) in acetic acid (10 ml) was heated under reflux for 2.5hours. The reaction mixture was poured onto ice-water (100 ml) andneutralized with saturated aqueous sodium bicarbonate solution.Resultant precipitates were collected by filtration, washed with water,and recrystallized from ethyl acetate to give crystals of3-acetamido-2-phenylpyrazolo[1,5-a]pyridine (304 mg).

mp: 188° to 189° C.

IR (Nujol): 3170, 1640, 1530 cm⁻¹

NMR (CDCl₃, δ): 2.20 (3H, s), 6.87 (1H, td, J=6.5 Hz and 1.0 Hz),7.07-8.10 (8H, m), 8.27-8.57 (1H, m)

Analysis Calcd. for C₁₅ H₁₃ N₃ O: C 71.69, H 5.21, N 16.72; Found: C71.68, H 4.75, N 16.75.

MS: 251 (M⁺)

EXAMPLE 27 ##STR34##

A mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (1.00 g), zincpowder and concentrated hydrochloric acid (0.4 ml) in ethanol (10 ml)was heated under reflux for 3 hours.

Ethanol was evaporated in vacuo. The mixture was neutralized withaqueous saturated sodium bicarbonate solution (20 ml) and extracted withchloroform (30 ml×2). The combined extracts were washed with saturatedsodium chloride aqueous solution (20 ml), dried over magnesium sulfateand evaporated in vacuo. The crude crystals were recrystallized fromethyl acetate to give 3-amino-2-phenylpyrazolo[1,5-a]pyridine (531 mg).

mp: 155° to 157° C.

IR (Nujol): 3360, 3250, 1625 cm⁻¹

NMR (CDCl₃, δ): 3.13 (2H, s), 6.60 (1H, td, J=7.0 Hz and 2.0 Hz), 6.97(1H, td, J=7.0 Hz and 1.0 Hz), 7.27-8.10 (2H, m), 7.83-8.10 (2H, m),8.32 (1H, dd, J=7.0 Hz and 1.0 Hz)

Analysis Calcd. for C₁₃ H₁₁ N₃ : C 74.62, H 5.30, N 20.08; Found: C74.88, H 4.85, N 20.15.

EXAMPLE 28 ##STR35##

2-Ethoxycarbonylacetyl chloride (0.445 g) was added dropwise to asolution of triethylamine (0.298 g) and3-amino-2-phenylpyrazolo[1,5-a]pyridine (0.560 g) in methylene chloride(10 ml) with ice-cooling.

The mixture was left at room temperature overnight. The mixture waspoured into saturated sodium chloride aqueous solution (20 ml) andextracted with chloroform (20 ml×2). The combined extracts were washedwith saturated sodium chloride aqueous solution (20 ml), dried overmagnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (20 g) with chloroform as an eluent. Thefractions containing the objective compound were combined, evaporated invacuo and recrystallized from ethyl acetate to give crystals of3-(2-ethoxycarbonylacetamido)-2-phenylpyrazolo[1,5-a]pyridine (0.48 g).

mp: 160°-161° C.

IR (Nujol) 3250, 1740, 1650, 1570 cm⁻¹

NMR (CDCl₃, δ): 1.32 (3H, t, J=7.0 Hz), 3.55 (2H, s), 4.30 (2H, q, J=7.0Hz), 6.79 (1H, td, J=7.0 Hz and 1.5 Hz), 7.20 (1H, t, J=7.0 Hz),7.38-7.67 (4H, m), 7.70-8.10 (2H, m), 8.45 (1H, d, J=7.0 Hz), 8.75 (1H,broad s)

Analysis Calcd for C₁₈ H₁₇ N₃ O₃ : C 66.86, H 5.30, N 13.00; C 67.21, H4.83, N 13.10.

EXAMPLE 29 ##STR36##

3-(1-Semicarbazonoethyl)-2-phenylpyrazolo[1,5-a]pyridine was obtainedaccording to a similar manner to that of Example 1.

mp: 185° to 194° C.

IR (Nujol): 3750, 3200, 1685, 1580 cm⁻¹

NMR (DMSO-d₆, δ): 1.95 (1.5H , s), 2.10 (1.5H, s), 6.10-6.33 (2H, m),6.80-7.15 (1H, m), 7.29-8.00 (6H, m), 9.28 (1H, s), 8.55-8.90 (1H, m)

MS: 293 (M⁺)

The following compounds (Examples 30 to 38) were obtained according to asimilar manner to that of Example 2.

EXAMPLE 30 ##STR37##

4-Methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (E and Z mixture)

mp: 164°-165° C.

IR (Nujol): 3150, 1660 cm⁻¹

NMR (DMSO-d₆, δ): 2.17 and 2.25 (Total 6H, s), 2.67 and 2.71 (Total 3H,s), 3.02 and 3.07 (Total 2H, s), 6.88-7.98 (7H, m), 8.46-8.86 (2H, m)

Analysis Calcd. for C₁₉ H₂₀ N₅ O: C 68.04, H 6.31, N 20.88; Found: C68.33, H 6.17, N 21.07.

EXAMPLE 31 ##STR38##

5-Methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (E and Z mixture)

mp: 196°-197° C.

IR (Nujol): 1675, 1640, 1600, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.27 and 2.38 (Total 6H, s), 2.49 (3H, broad s), 3.00and 3.52 (Total 3H, s), 7.02 (1H, broad d, J=7.0 Hz), 7.48-8.38 (6H, m),8.64-8.90 (2H, m)

Analysis Calcd. for C₁₉ H₂₁ N₅ O: C 68.24, H 6.03, N 20.94; Found: C67.96, H 6.21, N 20.68.

EXAMPLE 32 ##STR39##

7-Methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (single isomer)

mp: 151°-153° C.

IR (Nujol): 3300, 1660, 1620, 1590 cm⁻¹

NMR (CDCl₃, δ): 2.33 (6H, s), 2.82 (3H, s), 3.12 (2H, s), 6.82 (1H, d,J=6.5 Hz), 7.23-7.83 (6H, m), 8.37 (1H, s), 8.48 (1H, d, J=6.5 Hz), 9.93(1H, s)

Analysis Calcd. for C₁₉ H₂₁ N₅ O: C 68.04, H 6.31, N 20.88; Found: C68.29, H 6.20, N 20.29.

EXAMPLE 33 ##STR40##

2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (E and Z mixture)

mp: 202°-205° C.

IR (Nujol): 3450, 1660, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 2.30 and 2.36 (Total 6H, s), 3.05 and 3.52 (Total 2H,s), 7.17 (1H, t, J=7.0 Hz), 7.40-8.00 (5H, m), 8.00-9.00 (3H, m)

Analysis Calcd. for C₁₈ H₁₈ ClN₅ O: C 60.76, H 5.10, N 19.68; Found: C61.06, H 5.08, N 19.79.

MS: 354 (M⁺)

EXAMPLE 34 ##STR41##

2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (single isomer)

mp: 167°-168° C.

IR (Nujol): 3350, 1660, 1625, 1600 cm⁻¹

NMR (CDCl₃, δ): 2.30 (6H, s), 3.10 (3H, s), 6.99 (1H, t, J=7.0 Hz),7.30-7.77 (6H, m), 7.99 (1H, s), 8.53 (2H, d, J=7.0 Hz)

Analysis Calcd. for C₁₈ H₁₈ ClN₅ O: C 60.76, H 5.10, N 19.68; Found: C60.95, H 5.04, N 19.56.

MS: 355 (M⁺)

EXAMPLE 35 ##STR42##

2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone hydrochloride (E and Z mixture)

mp: 233°-236° C.

IR (Nujol): 1675, 1630, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 2.90 and 2.96 (Total 6H, s), 3.85 (3H, s), 4.07 and4.58 (Total 2H, s), 7.00-7.33 (3H, m), 7.40-7.83 (3H, m), 8.17-9.00 (3H,m)

Analysis Calcd. for C₁₉ H₂₁ N₅ O₂.HCl: C 58.84, H 5.72, N 18.06; Found:C 59.20, H 5.56, N 17.91.

EXAMPLE 36 ##STR43##

2-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (E and Z mixture)

mp: 145°-147° C.

IR (Nujol): 1660, 1625, 1605, 1575 cm⁻¹

NMR (DMSO-d₆, δ): 2.25 and 2.35 (Total 6H, s), 3.01 and 3.53 (Total 2H,s), 3.87 (3H, s), 7.05-7.67 (6H, m), 8.20-8.93 (3H, m)

Analysis Calcd. for C₁₉ H₂₁ N₅ O₂ : C 64.94, H 6.02, N 19.93; Found: C65.32, H 5.86, N 19.56.

MS: 351 (M⁺)

EXAMPLE 37 ##STR44##

2-(3-Nitrophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (E and Z mixture)

mp: 202°-206° C.

IR (Nujol): 1660, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 2.30 and 2.35 (Total 6H, s), 3.05 and 3.47 (Total 2H,s), 7.20 (1H, t, J=7.5 Hz), 7.60 (1H, t, J=7.5 Hz), 7.88 (1H, t, J=7.5Hz), 8.15-8.74 (5H, m), 8.94 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₁₈ H₁₈ N₆ O₃ : C 59.01, H 4.95, N 22.94; Found: C58.91, H 4.74, N 22.95.

EXAMPLE 38 ##STR45##

2-Isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde[2-(dimethylamino)acetyl]hydrazone (single isomer)

mp: 140°-141° C.

IR (Nujol): 1660, 1630, 1520 cm⁻¹

NMR (CDCl₃, δ): 1.42 (6H, d, J=6 Hz), 2.37 (6H, s), 3.13 (2H, s), 3.37(1H, septet, J=6.0 Hz), 6.85 (1H, td, J=6.5 Hz and 2.0 Hz), 7.33 (1H,td, J=6.5 Hz and 2.0 Hz), 8.37 (1H, d, J=6.5 Hz), 8.43 (1H, d, J=6.5Hz), 8.15 (1H, s), 10.00 (1H, broad s)

Analysis Calcd. for C₁₅ H₂₁ N₅ O: C 62.70, H 7.37, N 24.37; Found: C62.71, H 7.16, N 24.13.

The following compounds (Examples 39 to 55) were obtained according to asimilar manner to that of Example 22.

EXAMPLE 39 ##STR46##

N,N-Diethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3yl)acrylamide (transisomer)

IR (CHCl₃) 1640, 1595, 1520 cm⁻¹

NMR (CDCl₃, δ): 1.15 (6H, t, J=7 Hz), 3.10-3.78 (4H, m), 6.56 (1H, d,J=16 Hz), 6.86 (1H, td, J=7 Hz and 1Hz), 7.22-7.90 (7H, m), 8.02 (1H, d,J=16 Hz), 8.57 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₀ H₂₁ N₃ O.1/2H₂ O: C 73.14, H 7.05, N 12.79;Found: C 73.68, H 6.52, N 12.75.

MS: 319 (M⁺)

EXAMPLE 40 ##STR47##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methylpiperidine(trans isomer)

IR (CHCl₃) 1640, 1590, 1515 cm⁻¹

NMR (CDCl₃, δ): 1.27 (3H, d, J=6 Hz), 1.42-1.97 (6H, broad), 2.80-3.25(1H, m), 4.00-4.85 (2H, m), 6.66 (1H, d, J=16 Hz), 6.87 (1H, td, J=7 Hzand 1Hz), 7.21-7.83 (7H, m), 7.93 (1H, d, J=16 Hz), 8.52 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₂ H₂₃ N₃ O: C 76.49, H 6.71, N 12.16; Found: C75.48, H 6.80, N 12.06.

MS: 345 (M⁺)

EXAMPLE 41 ##STR48##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-acryloyl]-2-propylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.88-1.97 (13H, m), 1.66-3.24 (1H, broad), 3.70-5.20(2H, broad), 6.72 (1H, d, J=16 Hz), 6.92 (1H, td, J=7 Hz and 1 Hz),7.23-7.88 (7H, m), 8.00 (1H, d, J=16 Hz), 8.60 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O: C 77.18, H 7.29, N 11.25; Found: C76.46, H 7.19, N 11.13.

MS: 373 (M⁺)

EXAMPLE 42 ##STR49##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine(trans isomer)

mp: 143° to 145° C.

IR (Nujol): 3320, 1635, 1575, 1500 cm⁻¹

NMR (CDCl₃, δ): 1.64 (6H, broad), 2.70-3.33 (1H, broad), 3.33-4.33 (3H,m), 4.33-4.66 (1H, broad), 6.75 (1H, d, J=16 Hz), 6.78 (1H, t, J=6 Hz),7.13-7.86 (7H, m), 7.94 (1H, d, J=16 Hz), 8.45 (1H, d, J=6 Hz)

MS: 361 (M⁺)

Analysis Calcd. for C₂₂ H₂₃ N₃ O₂.1/2H₂ O: C 71.33, H 6.25, N 11.34;Found: C 72.11, H 6.31, N 11.38.

EXAMPLE 43 ##STR50##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-(2-hydroxyethyl)piperidine(trans isomer)

mp: 89° to 93° C.

IR (Nujol): 3400, 1640, 1590, 1530, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.93-2.30 (7H, m), 2.47-3.28 (2H, m), 3.40 (2H, t, J=6Hz), 3.90-5.03 (2H, m), 6.70 (1H, d, J=15 Hz), 6.90 (1H, td, J=7 Hz and1Hz), 7.22-7.80 (6H, m), 8.95 (1H, d, J=15 Hz), 8.53 (1H, d, J=7 Hz)

MS: 375 (M⁺)

Analysis Calcd. for C₂₃ H₂₅ N₃ O: C 73.58, H 6.71, N 11.19; Found: C73.44, H 6.70, N 10.95.

EXAMPLE 44 ##STR51##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine(trans isomer)

IR (film): 1725, 1635, 1585, 1505 cm⁻¹

NMR (CDCl₃, δ): 1.21 (3H, t, J=8 Hz), 1.33-2.00 (6H, m), 2.00-2.50 (1H,m), 3.00-3.50 (1H, m), 4.25 (2H, q, J=8 Hz), 5.25-5.60 (1H, m)

Analysis Calcd. for C₂₄ H₂₅ N₃ O₃.C₂ H₅ O: C 69.47, H 6.73, N 9.35;Found: C 69.42, H 6.70, N 9.59.

MS: 403 (M⁺)

EXAMPLE 45 ##STR52##

1-[2-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

mp: 133.5° to 134.5° C.

IR (Nujol) 1740, 1620, 1600, 1520 cm⁻¹

NMR (CDCl₃, δ): 0.90 (3H, t, J=7 Hz), 1.33-2.00 (8H, m), 1.80 (3H, d,J=1Hz), 2.70-3.33 (1H, m), 3.96-4.66 (2H, m), 6.62 (1H, s), 6.85 (1H,td, J=7 Hz and 1Hz), 7.13-7.70 (5H, m), 7.80-8.03 (2H, m), 8.57 (1H, d,J=7 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O: C 77.18, H 7.29, N 11.25; Found: C76.04, H 7.34, N 10.64.

MS: 373 (M⁺)

EXAMPLE 46 ##STR53##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2,2,6,6-tetramethylpiperidine(trans isomer)

mp: 158° to 159° C.

IR (Nujol): 1640, 1580, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.45 (12H, s), 1.78 (6H, s), 6.46 (1H, d, J=15 Hz), 6.72(1H, t, J=7 Hz), 7.08-7.80 (8H, m), 8.48 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₅ H₂₉ N₃ O: C 77.49, H 7.54, N 10.84; Found: C77.75, H 7.49, N 10.74.

EXAMPLE 47 ##STR54##

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpyrrolidine(trans isomer)

IR (Nujol): 1700, 1640, 1590, 1520 cm⁻¹

NMR (CDCl₃, δ): 1.77-2.15 (4H, m), 3.33 (3H, s), 3.20-3.72 (2H, m),4.00-4.60 (1H, broad), 6.90 (1H, td, J=8 Hz and 1Hz), 7.20-7.90 (8H, m),8.02 (1H, d, J=16 Hz), 8.57 (1H, d, J=8 Hz)

Analysis Calcd. for C₂₃ H₂₅ N₃ O₂.H₂ O: C 70.20, H 6.91, N 10.06; Found:C 70.05, H 6.69, N 9.93.

MS: 375 (M⁺)

[α]_(D) ²⁶.8 =-70.44 (c=0.978, EtOH)

EXAMPLE 48 ##STR55##

1-[(2E,4E)-5-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoyl]-2-ethylpiperidine

IR (Nujol): 1620, 1580, 1500 cm⁻¹

NMR (CDCl₃, δ): 0.88 (3H, t, J=6 Hz), 1.10-2.00 (8H, m), 2.50-3.33 (1H,m), 3.66-5.00 (2H, m), 6.42 (1H, d, J=15 Hz), 6.66-7.94 (l1H, m), 8.59(1H, d, J=7 Hz)

Analysis Calcd. for C₂₅ H₂₇ N₃ O: C 77.89, H 7.06, N 10.90; Found: C77.57, H 6.95, N 10.69.

EXAMPLE 49 ##STR56##

(2R)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

mp: 137° to 139° C.

IR (Nujol): 3470, 1620, 1580 cm⁻¹

NMR (CDCl₃, δ): 1.30-2.10 (6H, m), 2.60-3.20 (1H, m), 3.10-4.00 (2H, m),3.90-4.40 (1H, m), 4.40-5.10 (1H, m), 6.62 (1H, d, J=16.0 Hz), 6.87 (1H,t, J=7.5 Hz), 7.28 (1H, t, J=7.5 Hz), 7.38 (1H, t, J=7.5 Hz), 7.58-8.05(3H, m), 8.46 (1H, d, J=7.5 Hz), 8.64 (1H, d, J=5.5 Hz), 8.93 (1H, s)

Analysis Calcd. for C₂₂ H₂₄ N₄ O₂ : C 70.19, H 6.43, N 14.88; Found: C70.13, H 6.39, N 14.85.

MS: 376 (M⁺)

EXAMPLE 50 ##STR57##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)propionyl]-2-ethylpiperidine

IR (Nujol): 1620, 1520 cm⁻¹

NMR (CDCl₃, δ): 0.60-1.00 (3H, m), 1.20-1.90 (7H, m), 2.27-2.83 (4H, m),3.10-3.67 (3H, m), 4.40-4.64 (1H, m), 6.60-8.90 (8H, m), 8.47 (1H, d,J=7 Hz)

Analysis Calcd. for C₂₃ H₂₇ N₃ O: C 76.42, H 7.53, N 11.62; Found: C74.94, H 6.98, N 11.22.

MS: 361 (M⁺)

EXAMPLE 51 ##STR58##

N-Benzyl-N-methyl-3-(2-phenylpyrazolo[1,5-a]-pyridin-3-yl)acrylamide(trans isomer)

mp: 118° to 119° C.

IR (Nujol): 1610, 1510 cm⁻¹

NMR (CDCl₃, δ): 3.05 (3H, s), 4.64 (2H, s), 6.70 (1H, d, J=15 Hz), 6.90(1H, t, J=7 Hz), 7.10-8.00 (12H, m), 8.08 (1H, d, J=15 Hz), 8.54 (1H, d,J=8 Hz)

Analysis Calcd. for C₂₄ H₂₁ N₃ O: C 78.44, H 5.76, N 11.44; Found: C78.01, H 5.91, N 11.36.

MS: 367 (M⁺)

EXAMPLE 52 ##STR59##

3-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-azabicyclo[3.2.2]nonane(trans isomer)

mp: 113° to 115° C.

IR (Nujol): 1630, 1580, 1500 cm⁻¹

NMR (CDCl₃, δ): 1.67 (8H, m), 1.92-2.23 (2H, m) 3.50-4.00 (4H, m), 6.83(1H, d, J=15 Hz), 6.90 (1H, t, J=7.5 Hz), 7.23-7.93 (7H, m), 7.97 (1H,d, J=15 Hz), 8.56 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₄ H₂₅ N₃ O: C 77.59, H 6.78, N 11.31; Found: C77.57, H 6.96, N 11.32.

MS: 371 (M⁺)

EXAMPLE 53 ##STR60##

7-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-7-azabicyclo[2.2.1]heptane(trans isomer)

mp: 155.5° to 156.5° C.

IR (Nujol): 1635, 1590, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.25-2.00 (8H, m), 4.00-4.90 (2H, broad), 6.52 (1H, d,J=16 Hz), 6.90 (1H, td, J=7 Hz and 1Hz), 7.20-8.83 (7H, m), 7.95 (1H, d,J=16 Hz), 8.56 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₂ H₂₁ N₃ O: C 76.94, H 6.16, N 12.24; Found: C77.28, H 6.05, N 12.54.

MS: 343 (M⁺)

EXAMPLE 54 ##STR61##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]perhydro-1H-azepine1/2 fumalate (trans isomer)

mp: 146°-147° C.

IR (Nujol): 1685, 1635, 1580, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-1.90 (8H, broad), 3.35-3.80 (4H, m), 6.65 (2H,s), 6.82 (1H, d, J=15 Hz), 7.13 (1H, t, J=7 Hz), 7.42-7.90 (7H, m), 8.12(1H, d, J=8 Hz), 8.90 (1H, d, J=7 Hz), 12.30-13.20 (1H, broad)

Analysis Calcd. for C₂₄ H₂₅ N₃ O₃.1/2H₂ O: C 69.88, H 6.59, N 10.19;Found: C 70.39, H 6.01, N 9.99.

MS: 345 (M⁺)

EXAMPLE 55 ##STR62##

1-[2-Bromo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine

NMR (CDCl₃, δ): 0.93 (3H, t, J=7.0 Hz), 1.45-2.10 (8H, m), 2.42-3.37(1H, m), 4.00-4.70 (2H, m), 6.87 (1H, td, J=7.0 Hz and 2.0 Hz),7.67-7.95 (8H, m), 8.52 (1H, dd, J=6.5 Hz and 1.0 Hz)

MS: 437, 439 (M⁺)

EXAMPLE 56 ##STR63##

Thionyl chloride (240 mg) was added dropwise to a stirred mixture of2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid [compound (I)] (320mg) and N,N-dimethylformamide (one drop) in chloroform (10 ml), and thenstirred under reflux for 4 hours.

After cooling the mixture, chloroform was evaporated in vacuo to giveacid chloride of compound (I).

Triethylamine (338 mg) was added to a suspension of the acid chloride ofcompound (I) in methylene chloride (10 ml) under ice-cooling, and tothis suspension a solution of 2-ethylpiperidine in methylene chloridewas added dropwise. The mixture was stirred under ice-cooling and stoodat room temperature overnight.

Saturated sodium chloride aqueous solution (20 ml) was added to themixture and extracted with chloroform (20 ml). The extract was driedover magnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (8 g) with chloroform as an eluent. Thefractions containing the objective compound were combined and evaporatedin vacuo to give1-(2-phenylpyrazolo[1,5-a]pyridin-3-ylcarbonyl)-2-ethylpiperidine (263mg).

mp: 182°-183° C.

IR (Nujol): 1630, 1600, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 0.69 (3H, t, J=7.0 Hz), 1.12-1.93 (8H, m), 2.73-3.17(1H, m), 3.69-4.45 (2H, m) 7.07 (1H, td, J=7.0 Hz and 2.0 Hz), 7.29-8.00(7H, m), 8.86 (1H, dd, J=7.0 Hz and 1.0 Hz)

Analysis Calcd. for C₂₁ H₂₃ N₃ O: C 75.65, H 6.95, N 12.60; Found: C75.75, H 7.01, N 12.66.

EXAMPLE 57 ##STR64##

A mixture of potassium hydroxide (0.5 g) and1-[2-bromo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(1.0 g) in ethanol (10 ml) was heated under reflux for 1.5 hours.

Ethanol was evaporated in vacuo and saturated sodium chloride aqueoussolution (20 ml) was added to the residue. The mixture was extractedwith ethyl acetate (20 ml×2). Combined extracts were washed withsaturated sodium chloride aqueous solution (20 ml), dried over magnesiumsulfate and evaporated in vacuo. The residue was chromatographed onsilica gel with chloroform as an eluent. The fractions containingobjective compound were combined and evaporated in vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propioloyl]-2-ethylpiperidine(0.71 g) as an oil.

IR (film): 2180, 1600, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.85 (3H, t, J=7.0 Hz), 1.30-2.00 (8H, m), 2.40-3.43(1H, m), 4.15-4.85 (2H, m), 6.90 (1H, td, J=7.0 Hz and 2.0 Hz),7.17-8.33 (7H, m), 8.50 (1H, d, J=7.0 Hz)

MS: 357 (M⁺)

EXAMPLE 58 ##STR65##

Lindler catalyst (21 mg) and quinoline (0.2 ml) were added to a solutionof1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propioloyl]-2-ethylpiperidine(410 mg) in ethyl acetate (10 ml). The mixture was shaken with hydrogen.

The catalyst was filtered off and ethyl acetate was evaporated in vacuo.The residue was chromatographed on silica gel with a mixture of n-hexaneand chloroform (1:1) as an eluent. The fractions containing objectivecompound were combined and evaporated in vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(cis isomer) (156.3 mg) as an oil.

IR (film): 1630, 1600, 1520 cm⁻¹

NMR (CDCl₃, δ): 0.80 (3H, t, J=7.0 Hz), 1.10-2.00 (8H, m), 2.30-3.20(1H, m), 3.70-4.83 (2H, m), 6.17 (1H, d, J=12.5 Hz), 6.57-8.03 (9H, m),8.48 (1H, dd, J=7.0 Hz and 1.0 Hz)

EXAMPLE 59 ##STR66##

Triethyl phosphonoacetate (14.56 g) was added dropwise to a suspensionof sodium hydride (60%, 2.60 g) in tetrahydrofuran (100 ml) withice-cooling. After being stirred at room temperature for 1 hour,2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (11.10 g) was added tothe mixture, and then stirred at room temperature for 1 hour.

The reaction mixture was poured onto ice-water and extracted with ethylacetate. The extract was washed with saturated sodium chloride aqueoussolution, dried over magnesium sulfate, and evaporated in vacuo to giveethyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer)(12.60 g).

mp: 130°-131° C.

IR (Nujol): 1690, 1615, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.30 (3H, t, J=6.0 Hz), 4.27 (2H, q, J=6.0 Hz), 6.30(1H, d, J=16.0 Hz), 6.88 (1H, td, J=6.0 Hz and 2.0 Hz), 7.16-8.33 (8H,m), 8.53 (1H, dd, J=8.0 Hz and 1.0 Hz)

The following compounds (Examples 60 and 61) were obtained according toa similar manner to that of Example 59.

EXAMPLE 60 ##STR67##

Ethyl 3-[2-(3-pyridyl)pyrazolo[1,5-a]pyridin-3-yl]acrylate (transisomer)

mp: 142° to 146° C.

IR (Nujol): 1690, 1620 cm⁻¹

NMR (CDCl₃, δ): 1.15 (3H, t, J=7.5 Hz), 4.08 (2H, q, J=7.5 Hz), 6.10(1H, d, J=16.0 Hz), 6.74 (1H, t, J=7.5 Hz), 7.03-7.40 (2H, m), 7.57-7.94(3H, m), 7.78 (1H, s), 7.57-7.94 (3H, m), 8.35 (1H, d, J=7.5 Hz), 8.52(1H, d, J=4.5 Hz)

EXAMPLE 61 ##STR68##

Ethyl (2E,4E)-5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoate

mp: 123.5° to 125.5° C.

IR (Nujol): 1705, 1605, 1500, 1260, 1235 cm⁻¹

NMR (CDCl₃, δ): 1.30 (3H, t, J=6 Hz), 4.23 (2H, q, J=6 Hz), 5.89 (1H, d,J=15 Hz), 6.98 (1H, d, J=15 Hz), 6.60-6.97 (1H, m), 7.23-7.90 (9H, m),8.55 (1H, d, J=8 Hz)

Analysis Calcd. for C₂₀ H₁₈ N₂ O₂ : C 75.45, H 5.70, N 8.80; Found: C75.87, H 5.57, N 8.90.

MS: 318 (M⁺)

EXAMPLE 62 ##STR69##

Sodium hydride (60%, 110 mg) was added to a solution of1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) intetrahydrofuran (5 ml) at 7° C. under nitrogen atmosphere. A solution of4-methyl-2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.50 g) intetrahydrofuran (5 ml) was added dropwise to the above solution at 10°C., and then stirred at room temperature for 1 hour. After evaporatingthe solvent, in vacuo saturated sodium chloride aqueous solution (20 ml)was added to the residue and extracted with ethyl acetate (20 ml×2).Combined extracts were washed with saturated sodium chloride aqueoussolution (20 ml), dried over magnesium sulfate and evaporated in vacuo.The residue was chromatographed on silica gel (20 g) with chloroform asan eluent. The fractions containing the objective compound were combinedand evaporated in vacuo to give1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer) (788 mg) as an oil.

IR (film): 1630, 1580, 1540 cm⁻¹

NMR (CDCl₃, δ): 0.71 (3H, t, J=7.0 Hz), 1.24-2.05 (8H, m), 2.79 (3H, s),6.29 (1H, d, J=16.0 Hz), 6.74 (1H, t, J=7.0 Hz), 7.05 (1H, d, J=7.0 Hz),7.24-7.93 (5H, m), 8.24 (1H, d, J=16.0 Hz), 8.38 (1H, d, J=7.0 Hz)

MS: 373 (M⁺)

EXAMPLE 63 ##STR70##

1-[3-(4-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer) was converted to1-[3-(4-methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer) according to a conventional manner.

mp: 124°-126° C.

IR (Nujol): 1685, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 0.62 (3H, t, J=7.0 Hz), 1.06-1.90 (8H, m), 3.43-4.43(2H, m), 6.24 (1H, d, J=16.0 Hz), 6.67 (1H, s), 6.94 (1H, t, J=7.0 Hz),7.24 (1H, t, J=7.0 Hz), 7.45-7.87 (5H, m), 8.05 (1H, d, J=16.0 Hz), 8.67(1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O.1/2C₄ H₄ O₄ : C 72.54, H 6.56, N 9.76;Found: C 71.65, H 6.43, N 9.52.

The following compounds (Examples 64 to 79) were obtained according to asimilar manner to that of Example 62 and/or Example 63.

EXAMPLE 64 ##STR71##

1-[3-(5-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

mp: 139°-141° C.

IR (Nujol): 1705, 1640 cm⁻¹

NMR (DMSO-d₆, δ): 0.82 (3H, t, J=7.0 Hz), 1.14-2.23 (8H, m), 2.50 (3H,s), 2.62-3.38 (1H, m), 4.07-4.70 (2H, m), 6.67 (1H, s), 6.88-7.20 (2H,m), 7.48-8.14 (7H, m), 8.81 (1H, d, J=7.0 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O.1/2C₄ H₄ O₄ : C 68.69, H 6.38, N 8.58;Found: C 68.81, H 6.37, N 8.58.

EXAMPLE 65 ##STR72##

1-[3-(7-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3yl)acryloyl]-2-ethylpiperidine(trans isomer)

mp: 95°-97° C.

IR (Nujol): 1620, 1570, 1535, 1505 cm⁻¹

NMR (CDCl₃, δ): 0.87 (3H, t, J=7.0 Hz), 1.23-2.00 (8H, m), 2.80 (3H, s),2.72-3.20 (1H, m), 3.83-4.67 (2H, m), 6.68 (1H, d, J=16.0 Hz), 6.77 (1H,d, J=7.0 Hz), 7.20 (1H, d, J=8.0 Hz), 7.37-7.83 (6H, m), 8.00 (1H, d,J=16.0 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O: C 77.18, H 7.29, N 11.25; Found: C77.15, H 7.18, N 11.14.

EXAMPLE 66 ##STR73##

1-[3-{2-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

mp: 115°-118° C.

IR (Nujol): 1635, 1605, 1575 cm⁻¹

NMR (DMSO-d₆, δ): 0.80 (3H, t, J=7.5 Hz), 1.20-1.90 (8H, m), 2.60-3.10(1H, m), 3.85 (3H, s), 3.90-4.60 (2H, m), 6.90 (1H, d, J=1.0 Hz),7.05-7.62 (6H, m), 7.76 (1H, d, J=16.0 Hz), 8.14 (1H, d, J=9.0 Hz), 8.87(1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O₂ : C 74.01, H 6.99, N 10.79; Found: C73.98, H 6.88, N 10.76.

EXAMPLE 67 ##STR74##

1-[3-{2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (CHCl₃) 1625, 1610, 1575 cm⁻¹

NMR (CDCl₃, δ): 0.77 (3H, t, J=7.0 Hz), 1.00-1.90 (8H, m), 2.50-3.20(1H, m), 3.82 (3H, s), 3.60-4.75 (2H, m), 6.57-8.06 (7H, m), 8.50 (1H.d, J=7 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O.1/4H₂ O: C 74.01, H 6.99, N 10.79;Found: C 73.09, H 6.98, N 10.47.

MS: 389 (M⁺)

EXAMPLE 68 ##STR75##

1-[3-{2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1635, 1580, 1515 cm⁻¹

NMR (CDCl₃, δ): 0.78 (3H, t, J=7.0 Hz), 1.22-1.93 (8H, m), 2.51-3.23(1H, m), 3.50-4.72 (2H, m), 6.65 (1H, d, J=16.0 Hz), 6.77-7.93 (8H, m),8.53 (1H, d, J=7.0 Hz)

MS: 393 (M⁺)

EXAMPLE 69 ##STR76##

1-[3-{2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

mp: 136°-140° C.

IR (Nujol): 1705, 1635, 1550, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 0.80 (3H, t, J=7.0 Hz), 1.30-1.90 (8H, m), 2.70-3.20(1H, m), 3.93-4.67 (2H, m), 6.57-7.96 (8H, m), 8.15 (1H, d, J=8.0 Hz),8.84 (1H, d, J=7.0 Hz)

Analysis Calcd. for C₂₃ H₂₄ ClN₃ O.1/2C₄ H₄ O₄ : C 66.44, H 5.80, N9.30; Found: C 66.30, H 5.65, N 9.35.

MS: 392 (M⁺)

EXAMPLE 70 ##STR77##

1-[3-{2-(3-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

mp: 156°-158° C.

IR (Nujol): 1710, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 0.74 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.60-3.20(1H, m), 4.00-4.60 (2H, m), 6.65 (1H, s), 6.94 (1H, d, J=16.0 Hz), 7.13(1H, t, J=7.5 Hz), 7.55 (1H, t, J=7.5 Hz), 7.70 (1H, d, J=16.0 Hz), 7.85(1H, t, J=7.5 Hz), 8.12 (2H, d, J=9.0 Hz), 8.35 (1H, d, J=9.0 Hz), 8.45(1H, s), 8.28 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₃ H₂₄ N₄ O₃.1/2C₄ H₄ O₄ : C 64.92, H 5.67, N12.11; Found: C 65.16, H 5.65, N 12.22.

EXAMPLE 71 ##STR78##

1-[3-{2-(4-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

mp: 170°-171° C.

IR (Nujol): 1635, 1575, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.82 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.51-3.10(1H, m), 3.70-4.70 (2H, m), 6.73 (1H, d, J=16.0 Hz), 6.90 (1H, t, J=7.5Hz), 7.33 (1H, t, J=7.5 Hz), 7.78 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=16.0Hz), 7.90 (2H, d, J=9.0 Hz), 8.33 (2H, d, J=9.0 Hz), 8.51 (1H, d, J=7.5Hz)

Analysis Calcd. for C₂₃ H₂₄ N₄ O₃ : C 68.30, H 5.98, N 13.85; Found: C68.33, H 5.96, N 13.71.

EXAMPLE 72 ##STR79##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)isocrotonoyl]-2-ethylpiperidine

NMR (CDCl₃, δ): 0.50-1.10 (3H, m), 1.08-2.30 (11H, m), 2.33-3.36 (1H,m), 3.36-4.20 (1H, m), 4.20-5.06 (1H, m), 6.14 (1H, s), 6.80 (1H, td,J=7 Hz and 1Hz), 7.07-8.00 (8H, m), 8.50 (1H, d, J=7 Hz)

MS: 373 (M⁺)

EXAMPLE 73 ##STR80##

1-[3-(7-Methoxy-2-phenylpyrazolo[1,5-a]pyridin-3yl)acryloyl]-2-ethylpiperidine(trans isomer)

mp: 122° to 123° C.

IR (Nujol): 1630, 1580, 1540, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.83 (3H, t, J=7.0 Hz), 1.25-2.02 (8H, m), 2.57-3.15(2H, m), 3.95-4.60 (2H, m), 4.15 (3H, s), 6.22 (1H, dd, J=6.0 Hz and 3.0Hz), 6.60 (1H, d, J=16.0 Hz), 7.26-8.12 (8H, m)

Analysis Calcd. for C₂₄ H₂₇ N₃ O₂ : C 74.01, H 6.99, N 10.79; Found: C74.15, H 6.96, N 10.83.

EXAMPLE 74 ##STR81##

1-[3-(4-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

mp: 132° to 133° C.

IR (Nujol): 1680, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 0.60 (3H, t, J=7.0 Hz), 1.0-1.80 (8H, m), 6.25 (1H, d,J=16.0 Hz), 6.67 (1H, s), 7.05 (1H, t, J=7.0 Hz), 7.43-7.93 (6H, m),8.17 (1H, d, J=16.0 Hz), 9.82 (1H, d, J=7.0 Hz)

Analysis Calcd. for C₂₃ H₂₄ ClN₃ O.1/2C₄ H₄ O₄ : C 66.44, H 5.80, N9.30; Found: C 65.97, H 5.75, N 9.03.

EXAMPLE 75 ##STR82##

1-[3-(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1630, 1580, 1505 cm⁻¹

NMR (CDCl₃, δ): 0.83 (3H, t, J=7.0 Hz), 1.37-1.87 (8H, m), 6.67 (1H, d,J=16.0 Hz), 7.15-8.05 (8H, m), 8.53 (1H, broad s)

MS: 393 (M⁺)

EXAMPLE 76 ##STR83##

1-[3-{2-(2-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer)

mp: 131°-133° C.

IR (Nujol): 1635, 1590, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.89 (3H, t, J=7.0 Hz), 1.50-1.80 (8H, m), 2.80-3.20(1H, m), 3.90-4.70 (2H, m), 6.88 (1H, d, J=7.0 Hz), 6.97 (1H, d, J=16.0Hz), 7.20-7.43 (2H, m), 7.70-8.12 (3H, m), 8.36 (1H, d, J=16.0 Hz), 8.51(1H, d, J=7.0 Hz), 8.80 (1H, d, J=6.0 Hz)

Analysis Calcd for C₂₂ H₂₄ N₄ O: C 73.31, H 6.71, N 15.54; Found: C73.50, H 6.55, N 15.50.

EXAMPLE 77 ##STR84##

(2S)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3}acryloyl]-2-ethylpiperidine(trans isomer)

NMR (CDCl₃, δ): 0.82 (3H, t, J=7.5 Hz), 1.20-1.90 (8H, m), 2.50-3.20(1H, m), 3.60-4.90 (2H, m), 6.65 (1H, d, J=16.0 Hz), 6.86 (1H, t, J=7.5Hz), 7.23 (1H, t, J=5.0 Hz), 7.37 (1H, t, J=7.5 Hz), 7.73 (1H, d, J=7.5Hz), 7.84 (1H, d, J=16.0 Hz), 8.00 (1H, d, J=6.0 Hz), 8.49 (1H, d, J=7.5Hz), 8.63 (1H, d, J=5.0 Hz), 8.95 (1H, s)

MS: 360 (M⁺)

EXAMPLE 78 ##STR85##

(2S)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

mp: 106° to 109° C.

IR (Nujol): 1700, 1635, 1580, 1560 cm⁻¹

NMR (CDCl₃ -DMSO-d₆, δ): 0.85 (3H, t, J=7.5 Hz), 1.30-1.90 (8H, m),2.40-3.20 (1H, m), 3.70-4.80 (2H, m), 6.72 (1H, d, J=16.0 Hz), 6.77 (2H,s), 6.91 (1H, t, J=7.5 Hz), 7.35 (1H, t, J=7.5 Hz), 7.24-7.55 (2H, m),7.80 (1H, d, J=7.5 Hz), 7.83 (1H, d, J=16.0 Hz), 8.04 (1H, d, J=7.5 Hz),8.53 (1H, d, J=7.5 Hz), 8.66 (1H, d, J=5.0 Hz), 8.95 (1H, s)

Analysis Calcd. for C₂₂ H₂₄ N₄ O.1/2C₄ H₄ O₄ : C 65.53, H 5.92, N 11.78;Found: C 64.43, H 5.98, N 11.50.

EXAMPLE 79 ##STR86##

1-[3-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

mp: 36°-38° C.

IR (Nujol): 1620 cm⁻¹

NMR (CDCl₃, δ): 0.95 (3H, t, J=7.0 Hz), 1.45 (6H, d, J=7.0 Hz),1.46-2.30 (8H, m), 2.77-3.37 (2H, m), 3.57 (1H, septet, J=7.0 Hz),4.25-4.97 (2H, m), 6.82 (1H, d, J=16.0 Hz), 6.73-7.07 (1H, m), 7.38 (1H,td, J=7.0 Hz and 1.0 Hz), 7.80 (1H, dd, J=7.0 Hz and 1.0 Hz), 8.05 (1H,d, J=16.0 Hz), 8.55 (1H, dd, J=7.0 Hz and 1.0 Hz)

Analysis Calcd. for C₂₀ H₂₇ N₃ O: C 73.81, H 8.36, N 12.91; Found: C72.53, H 8.19, N 12.56.

EXAMPLE 80 ##STR87##

1-(2-Diethoxyphosphorylacetyl)-2-ethylpiperidine (0.80 g) was addeddropwise to a suspension of sodium hydride (60%, 0.17 g) intetrahydrofuran (3 ml) at to 31° C. under nitrogen atomosphere, and then2-(3-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.80 g) wasadded portionwise to the mixture. After being stirred at 25° to 31° C.for 2 hours, tetrahydrofuran was evaporated in vacuo. Water was added tothe residue and extracted with ethyl acetate. Extract was washed withaqueous potassium carbonate solution (×2) and saturated sodium chlorideaqueous solution (×2), dried over magnesium sulfate and evaporated invacuo.

The residue was chromatographed on silica gel (22 g) with a mixture ofmethylene chloride and ethyl acetate (10:1) as an eluent. The fractionscontaining the objective compound was combined and evaporated in vacuoto give crystals of1-[3-{2-(3-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.37 g).

mp: 100°-104° C.

IR (Nujol): 1640, 1580, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.86 (3H, t, J=8.0 Hz), 1.30-1.90 (8H, m), 2.60-3.20(1H, m), 3.80-4.70 (2H, m), 6.65 (1H, d, J=16.0 Hz), 6.85 (1H, t, J=7.5Hz), 7.15-7.75 (6H, m), 7.88 (1H, d, J=16.0 Hz), 8.43 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₃ H₂₄ ClN₃ O: C 70.13, H 6.14, N 10.68; Found: C70.37, H 5.97, N 10.81.

MS: 393 (M⁺)

EXAMPLE 81 ##STR88##

A solution of 1-(2-diethoxyphosphorylacetyl)-2-ethylpiperidine (0.99 g)in tetrahydrofuran (1.8 ml) was added dropwise to a suspension of sodiumhydride (60%, 0.14 g) in tetrahydrofuran (4.5 ml) at 23° to 25° C. Afterbeing stirred at 24° C. for 30 minutes,2-(4-pyridyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.63 g) was addedto the mixture and then stirred at room temperature for 1 hour.

The reaction mixture was poured into aqueous potassium carbonatesolution and extracted with ethyl acetate (×2). The combined extractswere washed with saturated sodium chloride aqueous solution, dried overmagnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (25 g) with a mixture of chloroform andmethanol (100:1) as an eluent. The fractions containing objectivecompound were combined and evaporated in vacuo to give crystals. Thiswas recrystallized from a mixture of ethanol and water (1:1) to give1-[3-{2-(4-pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.38 g).

mp: 150° to 153° C.

IR (Nujol): 1640, 1605 cm⁻¹

NMR (CDCl₃, δ): 0.77 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.50-3.20(1H, m), 3.60-4.80 (2H, m), 6.65 (1H, d, J=16.0 Hz), 6.85 (1H, t, J=7.5Hz), 7.26 (1H, t, J=7.5 Hz), 7.33-7.97 (3H, m), 7.85 (1H, d, J=16.0 Hz),8.45 (1H, d, J=7.5 Hz), 8.67 (1H, d, J=5.0 Hz)

Analysis Calcd. for C₂₂ H₂₄ N₄ O: C 73.31, H 6.71, N 15.54; Found: C73.65, H 6.77, N 15.39.

The following compounds (Examples 82 and 83) were obtained according toa similar manner to that of Example 8.

EXAMPLE 82 ##STR89##

3-[2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl]acrylic acid (trans isomer)

mp: 251°-252° C.

IR (Nujol): 1680, 1620, 1600 cm⁻¹

NMR (CF₃ COOH, δ): 6.47 (1H, d, J=15.0 Hz), 7.25 (1H, t, J=6.5 Hz),7.60-8.22 (4H, m), 8.70-9 15 (4H, m)

EXAMPLE 83 ##STR90##

(2E,4E)-5-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoic acid

mp: 230°-230.5° C.

IR (Nujol): 1690, 1605, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 5.92 (1H, d, J=15 Hz), 6.93-7.87 (10H, m), 8.13 (1H,d, J=8 Hz), 8.83 (1H, d, J=8 Hz)

MS: 290 (M⁺)

EXAMPLE 84 ##STR91##

3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) wasobtained from ethyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate(trans isomer) according to a similar manner to that of Example 8.

The physical data were identical with those of the compound obtained inExample 8.

EXAMPLE 85 ##STR92##

2-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (transisomer) was obtained from 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehydeaccording to similar manners to those of Examples 7 and 8.

mp: 215° to 216° C.

IR (Nujol): 1700, 1630, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.80 (3H, s), 7.06 (1H, td, J=7 Hz and 1 Hz),7.33-7.90 (8H, m), 8.86 (1H, d, J=7 Hz)

MS: 278 (M⁺)

EXAMPLE 86 ##STR93##

A solution of bromine (1.65 g) in chloroform (5 ml) was added dropwiseto a solution of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate(trans isomer) (1.65 g) in chloroform (25 ml) at 5° to 10° C. Afterbeing stirred at room temperature for 2 hours and 40 minutes, chloroformwas evaporated in vacuo. 95% EtOH (15 ml) and potassium hydroxide (1.50g) were added to the residue, and then the mixture was heated underreflux for 4.5 hours.

Ethanol was evaporated in vacuo, and the residue was dissolved in 1Naqueous sodium hydroxide solution. Insoluble material was filtered off,and the filtrate was acidified with 5% hydrochloric acid. Resultantprecipitates were collected by filtration and washed with water andmethanol to give crystals of2-bromo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (1.29 g).

mp: 172° to 178° C. (dec.)

IR (Nujol): 1685, 1605 cm⁻¹

NMR (DMSO-d₆, δ): 7.11 (1H, td, J=7.0 Hz and 1.0 Hz), 7.37-7.93 (7H, m),8.38 (1H, s), 8.87 (1H, d, J=7.0 Hz)

Analysis Calcd. for C₁₆ H₁₁ BrN₂ O₂ : C 56.00, H 3.21, N 8.17; Found: C58.35, H 3.90, N 7.76.

EXAMPLE 87 ##STR94##

Thionyl chloride (0.38 ml) was added dropwise to a stirred mixture of3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) (1.06g) and N,N-dimethylformamide (2 drops) in methylene chloride (6 ml)under ice-cooling. After being stirred at room temperature for 1 hour.n-Butanol was added dropwise to the stirring mixture under ice-cooling.After being stirred at room temperature for 10 minutes, the reactionmixture was poured into ice-water (20 ml), made basic (pH 12) andextracted with methylene chloride. The extract was washed with water,saturated sodium chloride aqueous solution, dried over magnesiumsulfate, and evaporated.

The residue was recrystallized from a mixture of diisopropyl ethern-hexane to give n-butyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate(trans isomer) (1.08 g).

mp: 80° to 82° C.

IR (Nujol): 1690, 1620, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.03 (3H, t, J=7 Hz), 1.27-1.96 (4H, m), 4.25 (2H, t,J=7 Hz), 6.33 (1H, d, J=15 Hz), 6.97 (1H, td, J=7 Hz and 1 Hz),7.25-7.97 (7H, m), 8.00 (1H, d, J=15 Hz), 8.60 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₀ H₂₀ N₂ O₂ : C 74.98, H 6.29, N 8.74; Found: C75.11, H 6.32, N 8.69.

EXAMPLE 88 ##STR95##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine(trans isomer) (0.30 g) was added to a stirred solution oftetrahydrofuran (2 ml) and sodium hydride (62.8%, 0.04 g) withice-cooling. After 30 minutes, a solution of methyl iodide (0.14 g) intetrahydrofuran (2 ml) was added to that stirred solution at 0° C. Thereaction mixture was stirred for hours at room temperature, then pouredinto water (20 ml), extracted with chloroform (20 ml), dried overmagnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (20 g) with chloroform as an eluent. Thefractions containing the objective compound were combined and evaporatedin vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine(trans isomer) (0.30 g) as an oil.

IR (Nujol): 1640, 1590, 1510, 1440, 1415 cm⁻¹

NMR (CDCl₃, δ): 1.15-1.80 (6H, m), 2.35-3.20 (1H, broad), 3.40 (3H, s),3.90-4.80 (2H, broad), 6.70 (1H, d, J=16 Hz), 6.78 (1H, td, J=7 Hz and 1Hz), 7.00-7.77 (7H, m), 7.85 (1H, d, J=16 Hz), 8.45 (1H, d, J=7 Hz)

MS: 375 (M⁺)

EXAMPLE 89 ##STR96##

3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-methoxyethyl)piperidine(trans isomer) was obtained according to a similar manner to that ofExample 88.

mp: 139° to 140° C.

IR (Nujol): 1635, 1590, 1510 cm⁻¹

NMR (CDCl₃, δ): 1.40-2.20 (9H, m), 2.30-3.10 (1H, m), 3.30 (3H, s),3.95-5.05 (2H, m), 6.75-8.18 (10H, m), 8.55 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₄ H₂₇ N₃ O₂ : C 74.01, H 6.99, N 10.79; Found: C73.79, H 6.51, N 10.69.

MS: 389 (M⁺)

EXAMPLE 90 ##STR97##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine(trans isomer) (0.50 g) was added to a stirred solution of aceticanhydride (0.16 g) in pyridine (5 ml) at room temperature, and stirredat room temperature for 3 hours. Ethyl acetate was added to the reactionmixture and washed with 1N aqueous sodium hydroxide solution, water andsaturated sodium chloride aqueous solution, then dried over magnesiumsulfate and evaporated in vacuo. The residue was chromatographed onsilica gel (50 g) with a mixture of chloroform and acetone (20:1) as aneluent. The fractions containing the objective compound were combinedand evaporated in vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine(trans isomer) (0.35 g) as an oil.

IR (CHCl₃): 1740, 1640, 1590 cm⁻¹

NMR (CDCl₃, δ): 1.30-2.00 (8H, broad), 2.02 (3H, s), 2.65-3.15 (1H, m),3.90-4.90 (2H, m), 6.73 (1H, d, J=18 Hz), 6.94 (1H, dd, J=7.5 Hz and 1.5Hz), 7.23-7.85 (7H, m), 7.97 (1H, d, J=18 Hz), 8.53 (1H, d, J=7.5 Hz)

MS: 403 (M⁺)

EXAMPLE 91 ##STR98##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-acetoxyethyl)piperidine(trans isomer) was obtained according to a similar manner to that ofExample 90.

IR (CHCl₃): 1725, 1635, 1585, 1515 cm⁻¹

NMR (CDCl₃, δ): 1.00-2.36 (7H, m), 1.90 (3H, s), 2.48-3.30 (1H, broad),4.02 (2H, t, J=6 Hz), 4 4-5.0 (1H, broad), 6.65 (1H, d, J=16 Hz), 6.83(1H, td, J=6 Hz and 1 Hz), 7.18-7.80 (7H, m), 7.92 (1H, d, J=16 Hz),8.50 (1H, d, J=6 Hz)

Analysis Calcd. for C₂₅ H₂₇ N₃ O₃.1/2H₂ O: C 70.40, H 6.85, N 9.85,Found: C 70.96, H 6.59, N 9.71.

MS: 417 (M⁺)

EXAMPLE 92 ##STR99##

A mixture of1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine(trans isomer) (0.50 g) and 1N aqueous sodium hydroxide solution (5 ml)in methanol (5 ml) was refluxed for 3 hours. The reaction mixture wasevaporated to remove methanol, neutralized with 10% hydrochloric acidand extracted with chloroform. The extract was washed with saturatedsodium chloride aqueous solution, dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on silica gel (20g) with chloroform as an eluent. The fractions containing the objectivecompound were combined and evaporated in vacuo to give1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylicacid (trans isomer) (0.26 g) as an oil.

IR (Nujol): 3350, 1750, 1630, 1560, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 1.07 (3H, t, J=7 Hz), 1.20-1.85 (6H, broad), 2.00-2.45(1H, broad), 3.47 (2H, q, J=7 Hz), 3.90-4.75 (1H, broad), 4.75-5.30 (1H,m), 6.93 (1H, d, J=15 Hz), 7.12 (1H, t, J=7 Hz), 7.35-8.00 (7H, m), 8.18(1H, d, J=7 Hz), 8.80 (1H, d, J=7 Hz)

Analysis Calcd. for C₂₂ H₂₁ N₃ O₃.H₂ O: C 67.16, H 5.89, N 10.68; Found:C 66.59, H 6.01, N 9.94.

MS: 375 (M⁺)

EXAMPLE 93 ##STR100##

A solution of1-[3-{2-(3-nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (2.00 g) in ethanol (10 ml) was added dropwise to stirredmixture of iron powder (0.83 g) and ammonium chloride (0.08 g) inethanol (20 ml) and water (10 ml) at 45° C. The reaction mixture wasstirred at 69° C. for hours and 20 minutes.

Insoluble inorganic materials were filtered off and the solvent wasevaporated in vacuo. The residue was recrystallized from a mixture ofethanol and ethyl acetate (1:1) to give crystals of1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (1.36 g).

mp: 150°-151° C.

IR (Nujol): 3410, 3340, 3240, 1635, 1605 cm⁻¹

NMR (CDCl₃, δ): 0.82 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.50-3.50(2H, m), 3.80-4.70 (2H, m), 6.60-7.40 (7H, m), 7.74 (1H, d, J=9.0 Hz),7.93 (1H, d, J=16.0 Hz), 8.49 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₃ H₂₆ N₄ O: C 73.77, H 7.00, N 14.96; Found: C73.37, H 6.87, N 14.80.

MS: 374 (M⁺)

EXAMPLE 94 ##STR101##

1-[3-{2-(4-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) was obtained according to a similar manner to that ofExample 93.

IR (Nujol): 3335, 3220, 1635, 1605, 1580 cm⁻¹

NMR (CDCl₃, δ): 0.85 (3H, t, J=7.5 Hz), 1.30-1.90 (8H, m), 2.50-3.10(1H, m), 3.83 (1H, broad s), 3.90-4.70 (2H, m), 6.60-6.90 (3H, m), 7.25(1H, t, J=7.5 Hz), 7.42-7.80 (3H, m), 7.95 (1H, d, J=16.0 Hz), 8.48 (1H,d, J=7.5 Hz)

Analysis Calcd. for C₂₃ H₂₆ N₄ O: C 73.77, H 7.00, N 14.96; Found: C72.87, H 7.35, N 14.69.

MS: 374 (M⁺)

EXAMPLE 95 ##STR102##

A mixture of1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]-pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.80 g) and acetic anhydride (0.21 ml) in toluene (8 ml)was heated at 75° to 80° C. for 45 minutes.

The solvent was evaporated in vacuo. Water was added to the residue andextracted with methylene chloride. Combined extracts were washed withsaturated sodium chloride aqueous solution, dried over magnesium sulfateand evaporated in vacuo to give crystals of1-[3-{2-(3-acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.33 g).

mp: 225°-231° C.

IR (Nujol): 3380, 1685, 1635 cm⁻¹

NMR (CDCl₃ :DMSO=1:1, δ): 0.80 (3H, t, J=7.5 Hz), 1.20-1.90 (8H, m),2.05 (3H, s), 2.60-3.20 (1H, m), 3.90-4.60 (2H, m), 6.80 (1H, d, J=16.0Hz), 7.02 (1H, t, J=7.5 Hz), 7.20-7.56 (3H, m), 7.60-8.10 (4H, m), 8.67(1H, d, J=7.5 Hz), 10.00 (1H, s)

Analysis Calcd. for C₂₅ H₂₈ N₄ O₂ : C 72.09, H 6.78, N 13.45; Found: C71.49, H 6.48, N 13.33.

EXAMPLE 96 ##STR103##

1-[3-{2-(4-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) was obtained according to a similar manner to that ofExample 95.

IR (Nujol): 3250, 1685, 1635, 1595 cm⁻¹

NMR (DMSO-d₆, δ): 0.73 (3H, t, J=7.5 Hz), 1.10-1.80 (8H, m), 2.03 (3H,s), 2.60-3.10 (1H, m), 3.20-4.60 (2H, m), 6.70-7.90 (8H, m), 8.09 (1H,d, J=9.0 Hz)

MS: 416 (M⁺)

EXAMPLE 97 ##STR104##

Methanesulfonyl chloride (0.59 g) was added dropwise to a stirredsolution of1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (1.20 g) and triethylamine (0.52 g) inmethylene chloride (7.2 ml) with ice-cooling. After being stirred atroom temperature for 6 hours, the reaction mixture was washed twice withwater and once with saturated sodium chloride aqueous solution, driedover magnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (22 g) with chloroform as an eluent. Thefractions containing the objective compound were combined and evaporatedin vacuo to give crystals of1-[3-{2-(3-methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.36 g).

mp: 188°-190° C.

IR (Nujol): 3080, 1635, 1610 cm⁻¹

NMR (DMSO-d₆, δ): 0.75 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.60-3.20(1H, m), 3.06 (3H, s), 3.90-4.70 (2H, m), 6.92 (1H, d, J=16.0 Hz), 7.10(1H, t, J=7.5 Hz), 7.17-7.66 (5H, m), 7.73 (1H, d, J=16.0 Hz), 8.12 (1H,d, J=9.0 Hz), 8.87 (1H, d, J=7.5 Hz), 10.01 (1H, s)

Analysis Calcd for C₂₄ H₂₈ N₄ O₃ S: C 63.69, H 6.24, N 12.38; Found: C63.52, H 6.44, N 12.29.

MS: 452 (M⁺)

EXAMPLE 98 ##STR105##

Methyl chloroformate (0.40 g) was added dropwise to a stirred solutionof1-[3-{2-(3-aminophenyl)pyrazolo-[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (1.20 g) and triethylamine (0.44 g) in methylene chloride(7.2 ml) with ice-cooling.

After being stirred at room temperature for 6 hours, the reactionmixture was poured onto aqueous potassium carbonate solution andextracted with ethyl acetate. The extract was washed with water andsaturated sodium chloride aqueous solution, dried over magnesium sulfateand evaporated in vacuo to give crystals of1-[3-{2-(3-methoxycarbonylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.31 g).

mp: 143°-145° C.

IR (Nujol): 3260, 1725, 1640 cm⁻¹

NMR (DMSO-d₆, δ): 0.73 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.60-3.10(1H, m), 3.65 (3H, s), 3.80-4.60 (2H, m), 6.85 (1H, d, J=16.0 Hz), 7.08(1H, t, J=7.5 Hz), 7.30 (1H, d, J=7.5 Hz), 7.33-7.70 (4H, m), 7.80 (1H,d, J=2.0 Hz), 8.10 (1H, d, J=9.0 Hz), 8.80 (1H, d, J=7.5 Hz), 9.84 (1H,s)

Analysis Calcd. for C₂₅ H₂₈ N₄ O₃ : C 69.42, H 6.52, N 12.95; Found: C69.18, H 6.57, N 12.87.

MS: 432 (M⁺)

EXAMPLE 99 ##STR106##

A solution of methyliodide (0.84 g) in N,N-dimethylformamide (2 ml) wasadded dropwise to a stirred mixture of1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (1.50 g) and powdered potassium carbonate (0.28 g) inN,N-dimethylformamide (10 ml) at room temperature. After being stirredat room temperature for 2 hours and 50 minutes, the reaction mixture waspoured into water and extracted with ethyl acetate. The extract waswashed with water and saturated sodium chloride aqueous solution, driedover magnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (36 g) with a mixture of methylenechloride and acetonitrile (5:1) as an eluent. The fractions containingmajor product were combined and evaporated in vacuo to give crystals of1-[3-{2-(3-methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer) (0.21 g).

mp: 135°-141° C.

IR (Nujol): 3500, 1635, 1580, 1510 cm⁻¹

NMR (CDCl₃, δ): 0.78 (3H, t, J=7.5 Hz), 1.20-1.80 (8H, m), 2.84 (3H, s),2.60-3.20 (1H, m), 3.70-4.70 (2H, m), 6.68 (1H, d, J=16.0 Hz), 6.68-7.08(4H, m), 7.27 (2H, t, J=7.5 Hz), 7.72 (1H, d, J=9.0 Hz), 7.94 (1H, d,J=16.0 Hz), 8.49 (1H, d, J=7.5 Hz)

Analysis Calcd. for C₂₄ H₂₈ N₄ O: C 74.20, H 7.26, N 14.42; Found: C74.07, H 7.45, N 14.30.

The fractions containing minor product were combined and evaporated invacuo to give crystals of1-[3-{2-(3-dimethylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)(0.18 g).

mp: 180° to 184° C.

IR (Nujol): 1640, 1600 cm⁻¹

NMR (CDCl₃, δ): 0.82 (3H, t, J=7.5 Hz), 2.60-3.10 (1H, m), 3.70-4.60(2H, m), 6.67 (1H, d, J=16.0 Hz), 6.75-7.12 (4H, m), 7.28 (1H, t, J=7.5Hz), 7.78 (1H, d, J=9.0 Hz), 7.95 (1H, d, J=16.0 Hz), 8.53 (1H, d, J=7.5Hz)

Analysis Calcd. for C₂₅ H₃₀ N₄ O: C 74.60, H 7.51, N 13.92; Found: C74.18, H 6.87, N 14.20.

MS: 402 (M⁺)

The following compounds (Examples 100 to 131) were obtained according toa similar manner to that of Example 22.

EXAMPLE 100

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(cis isomer)

IR (film): 1630, 1600, 1520 cm⁻¹

EXAMPLE 101

1-[3-(4-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1630, 1580, 1540 cm⁻¹

EXAMPLE 102

1-[3-(5-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1640 cm⁻¹

EXAMPLE 103

1-[3-(7-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1620, 1570, 1535, 1505 cm⁻¹

EXAMPLE 104

1-[3-{2-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1605, 1575 cm⁻¹

EXAMPLE 105

1-[3-{2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (CHCl₃): 1625, 1610, 1575 cm⁻¹

EXAMPLE 106

1-[3-{2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1635, 1580, 1515 cm⁻¹

EXAMPLE 107

1-[3-{2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1635, 1550, 1510 cm⁻¹

EXAMPLE 108

1-[3-{2-(3-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1710, 1635 cm⁻¹

EXAMPLE 109

1-[3-{2-(4-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1575, 1510 cm⁻¹

EXAMPLE 110

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)isocrotonoyl]-2-ethylpiperidine

MS: 373 (M⁺)

EXAMPLE 111

1-[3-(7-Methoxy-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1630, 1580, 1540, 1510 cm⁻¹

EXAMPLE 112

1-[3-(4-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1680, 1620 cm⁻¹

EXAMPLE 113

1-[3-(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1630, 1580, 1505 cm⁻¹

EXAMPLE 114

1-[3-{2-(2-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 115

(2S)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

MS: 360 (M⁺)

EXAMPLE 116

1-[3-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1620 cm⁻¹

EXAMPLE 117

1-[3-{2-(3-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 118

1-[3-{2-(4-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1605 cm⁻¹

EXAMPLE 119

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine(trans isomer)

IR (Nujol): 1640, 1590, 1510, 1440, 1415 cm⁻¹

EXAMPLE 120

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-methoxyethyl)piperidine(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 121

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine(trans isomer)

IR (CHCl₃): 1740, 1640, 1590 cm⁻¹

EXAMPLE 122

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-acetoxyethyl)piperidine(trans isomer)

IR (CHCl₃): 1725, 1635, 1585, 1515 cm⁻¹

EXAMPLE 123

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylicacid (trans isomer)

IR (Nujol): 3350, 1750, 1630, 1560, 1510 cm⁻¹

EXAMPLE 124

1-[3-{2-(3-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3410, 3340, 3240, 1635, 1605 cm⁻¹

EXAMPLE 125

1-[3-{2-(4-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3335, 3220, 1635, 1605, 1580 cm⁻¹

EXAMPLE 126

1-[3-{2-(3-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3380, 1685, 1635 cm⁻¹

EXAMPLE 127

1-[3-{2-(4-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3250, 1685, 1635, 1595 cm⁻¹

EXAMPLE 128

1-[3-{2-(3-Methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3080, 1635, 1610 cm⁻¹

EXAMPLE 129

1-[3-{2-(3-Methoxycarbonylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3260, 1725, 1640 cm⁻¹

EXAMPLE 130

1-[3-{2-(3-Methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3500, 1635, 1580, 1510 cm⁻¹

EXAMPLE 131

1-[3-{2-(3-Dimethylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1600 cm⁻¹

The following compounds (Examples 132 to 174) were obtained according toa similar manner to that of Example 62 (and Example 63).

EXAMPLE 132

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1635, 1580, 1540, 1510 cm⁻¹

EXAMPLE 133

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]pyrrolidine (transisomer)

IR (Nujol): 1640, 1590 cm⁻¹

EXAMPLE 134

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine (transisomer)

IR (Nujol): 1630, 1580 cm⁻¹

EXAMPLE 135

4-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]morpholine (transisomer)

IR (Nujol): 1625, 1580 cm⁻¹

EXAMPLE 136

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-methylpiperazinehydrochloride (trans isomer)

IR (Nujol): 2400, 1650, 1580, 1500 cm⁻¹

EXAMPLE 137

N-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3275, 1640, 1605 cm⁻¹

EXAMPLE 138

N-Isopropyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3275, 1640, 1600 cm⁻¹

EXAMPLE 139

N,N-Dimethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 1640, 1590 cm⁻¹

EXAMPLE 140

N-(Tricyclo[3.3.1.1³.7]decan-1-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3280, 1650, 1590, 1535, 1500 cm⁻¹

EXAMPLE 141

(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

EXAMPLE 142

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

EXAMPLE 143

(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3350, 1640, 1575, 1520 cm⁻¹

EXAMPLE 144

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR(CHCl₃): 3330, 1635, 1570, 1520 cm⁻¹

EXAMPLE 145

(2RS)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3280, 1625, 1560, 1510 cm⁻¹

EXAMPLE 146

N,N-Diethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (CHCl₃): 1640, 1595, 1520 cm⁻¹

EXAMPLE 147

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methylpiperidine(trans isomer)

IR (CHCl₃): 1640, 1590, 1515 cm⁻¹

EXAMPLE 148

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-propylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 149

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine(trans isomer)

IR (Nujol): 3320, 1635, 1575, 1500 cm⁻¹

EXAMPLE 150

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3400, 1640, 1590, 1530, 1510 cm⁻¹

EXAMPLE 151

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine(trans isomer)

IR (film): 1725, 1635, 1585, 1505 cm⁻¹

EXAMPLE 152

1-[2-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1740, 1620, 1600, 1520 cm⁻¹

EXAMPLE 153

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2,2,6,6-tetramethylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 154

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpyrrolidine(trans isomer)

IR (Nujol): 1700, 1640, 1590, 1520 cm⁻¹

EXAMPLE 155

1-[(2E,4E)-5-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoyl]-2-ethylpiperidine

IR (Nujol): 1620, 1580, 1500 cm⁻¹

EXAMPLE 156

(2R)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3470, 1620, 1580 cm⁻¹

EXAMPLE 157

N-Benzyl-N-methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide(trans isomer)

IR (Nujol): 1610, 1510 cm⁻¹

EXAMPLE 158

3-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-azabicyclo[3.2.2]nonane(trans isomer)

IR (Nujol): 1630, 1580, 1500 cm⁻¹

EXAMPLE 159

7-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-7-azabicyclo[2.2.1]heptane(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 160

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]perhydro-1H-azepine1/2 fumalate (trans isomer)

IR (Nujol): 1685, 1635, 1580, 1520 cm⁻¹

EXAMPLE 161

n-Butyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer)

IR (Nujol): 1690, 1620, 1510 cm⁻¹

EXAMPLE 162

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine(trans isomer)

IR (Nujol): 1640, 1590, 1510, 1440, 1415 cm⁻¹

EXAMPLE 163

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-methoxyethyl)piperidine(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 164

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine(trans isomer)

IR (CHCl₃): 1740, 1640, 1590 cm⁻¹

EXAMPLE 165

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-acetoxyethyl)piperidine(trans isomer)

IR (CHCl₃): 1725, 1635, 1585, 1515 cm⁻¹

EXAMPLE 166

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylicacid (trans isomer)

IR (Nujol): 3350, 1750, 1630, 1560, 1510 cm⁻¹

EXAMPLE 167

1-[3-{2-(3-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3410, 3340, 3240, 1635, 1605 cm⁻¹

EXAMPLE 168

1-[3-{2-(4-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3335, 3220, 1635, 1605, 1580 cm⁻¹

EXAMPLE 169

1-[3-{2-(3-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3380, 1685, 1635 cm⁻¹

EXAMPLE 170

1-[3-{2-(4-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3250, 1685, 1635, 1595 cm⁻¹

EXAMPLE 171

1-[3-{2-(3-Methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperdine(trans isomer)

IR (Nujol): 3080, 1635, 1610 cm⁻¹

EXAMPLE 172

1-[3-{2-(3-Methoxycarbonylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3260, 1725, 1640 cm⁻¹

EXAMPLE 173

1-[3-{2-(3-Methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3500, 1635, 1580, 1510 cm⁻¹

EXAMPLE 174

1-[3-{2-(3-Dimethylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1600 cm⁻¹

The following compounds (Examples 175 to 238) were obtained according toa similar manner to that of Example 25.

EXAMPLE 175

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1635, 1580, 1540, 1510 cm⁻¹

EXAMPLE 176

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]pyrrolidine (transisomer)

IR (Nujol): 1640, 1590 cm⁻¹

EXAMPLE 177

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine (transisomer)

IR (Nujol): 1630, 1580 cm⁻¹

EXAMPLE 178

4-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]morpholine (transisomer)

IR (Nujol): 1625, 1580 cm⁻¹

EXAMPLE 179

N-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3275, 1640, 1605 cm⁻¹

EXAMPLE 180

N-Isopropyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3275, 1640, 1600 cm⁻¹

EXAMPLE 181

N,N-Dimethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 1640, 1590 cm⁻¹

EXAMPLE 182

N-(Tricyclo[3.3.1.1³.7]decan-1-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (Nujol): 3280, 1650, 1590, 1535, 1500 cm⁻¹

EXAMPLE 183

(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

EXAMPLE 184

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 2930, 2860, 1635, 1585 cm⁻¹

EXAMPLE 185

(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3350, 1640, 1575, 1520 cm⁻¹

EXAMPLE 186

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (CHCl₃): 3330, 1635, 1570, 1520 cm⁻¹

EXAMPLE 187

(2RS)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3280, 1625, 1560, 1510 cm⁻¹

EXAMPLE 188

N,N-Diethyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide (transisomer)

IR (CHCl₃): 1640, 1595, 1520 cm⁻¹

EXAMPLE 189

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methylpiperidine(trans isomer)

IR (CHCl₃): 1640, 1590, 1515 cm⁻¹

EXAMPLE 190

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-propylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 191

1-[3-(2-Phenylpyrazolc[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine(trans isomer)

IR (Nujol): 3320, 1635, 1575, 1500 cm⁻¹

EXAMPLE 192

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3400, 1640, 1590, 1530, 1510 cm⁻¹

EXAMPLE 193

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine(trans isomer)

IR (film): 1725, 1635, 1585, 1505 cm⁻¹

EXAMPLE 194

1-[2-Methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1740, 1620, 1600, 1520 cm⁻¹

EXAMPLE 195

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2,2,6,6-tetramethylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 196

(2S)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpyrrolidine(trans isomer)

IR (Nujol): 1700, 1640, 1590, 1520 cm⁻¹

EXAMPLE 197

1-[(2E,4E)-5-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoyl]-2-ethylpiperidine

IR (Nujol): 1620, 1580, 1500 cm⁻¹

EXAMPLE 198

(2R)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer)

IR (Nujol): 3470, 1620, 1580 cm⁻¹

EXAMPLE 199

N-Benzyl-N-methyl-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylamide(trans isomer)

IR (Nujol): 1610, 1513 cm⁻¹

EXAMPLE 200

3-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-azabicyclo[3.2.2.]nonane(trans isomer)

IR (Nujol): 1630, 1580, 1500 cm⁻¹

EXAMPLE 201

7-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-7-azabicyclo[2.2.1]heptane(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 202

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]perhydro-1H-azepine1/2 fumalate (trans isomer)

IR (Nujol): 1685, 1635, 1580, 1520 cm⁻¹

EXAMPLE 203

1-[2-Bromo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine

MS: 437, 439 (M⁺)

EXAMPLE 204

Ethyl 3-[2-(3-pyridyl)pyrazolo[1,5-a]pyridin-3-yl]acrylate (transisomer)

IR (Nujol): 1690, 1620 cm⁻¹

EXAMPLE 205

Ethyl (2E, 4E)-5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2,4-pentadienoate

IR (Nujol): 1705, 1605, 1500, 1260, 1235 cm⁻¹

EXAMPLE 206

1-[3-(4-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1630, 1580, 1540 cm⁻¹

EXAMPLE 207

1-[3-(5-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1640 cm⁻¹

EXAMPLE 208

1-[3-(7-Methyl-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1620, 1570, 1535, 1505 cm⁻¹

EXAMPLE 209

1-[3-{2-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1605, 1575 cm⁻¹

EXAMPLE 210

1-[3-{2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (CHCl₃): 1625, 1610, 1575 cm⁻¹

EXAMPLE 211

1-[3-{2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1635, 1580, 1515 cm⁻¹

EXAMPLE 212

1-[3-{2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1705, 1635, 1550, 1510 cm⁻¹

EXAMPLE 213

1-[3-{2-(3-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1710, 1635 cm⁻¹

EXAMPLE 214

1-[3-{2-(4-Nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1575, 1510 cm⁻¹

EXAMPLE 215

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)isocrotonoyl]-2-ethylpiperidine

MS: 373 (M⁺)

EXAMPLE 216

1-[3-(7-Methoxy-2-pherylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1630, 1580, 1540, 1510 cm⁻¹

EXAMPLE 217

1-[3-(4-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine1/2 fumalate (trans isomer)

IR (Nujol): 1680, 1620 cm⁻¹

EXAMPLE 218

1-[3-(6-Chloro-2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (film): 1630, 1580, 1505 cm⁻¹

EXAMPLE 219

1-[3-{2-(2-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 220

(2S)-1-[3-{2-(3-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

MR: 360 (M⁺)

EXAMPLE 221

1-[3-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1620 cm⁻¹

EXAMPLE 222

1-[3-{2-(3-Chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1580, 1510 cm⁻¹

EXAMPLE 223

1-[3-{2-(4-Pyridyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1605 cm⁻¹

EXAMPLE 224

n-Butyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer)

IR (Nujol): 1690, 1620, 1510 cm⁻¹

EXAMPLE 225

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine(trans isomer)

IR (Nujol): 1640, 1590, 1510, 1440, 1415 cm⁻¹

EXAMPLE 226

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-methoxyethyl)piperidine(trans isomer)

IR (Nujol): 1635, 1590, 1510 cm⁻¹

EXAMPLE 227

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine(trans isomer)

IR (CHCl₃): 1740, 1640, 1590 cm⁻¹

EXAMPLE 228

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-acetoxyethyl)piperidine(trans isomer)

IR (CHCl₃): 1725, 1635, 1585, 1515 cm⁻¹

EXAMPLE 229

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylicacid (trans isomer)

IR (Nujol): 3350, 1750, 1630, 1560, 1510 cm⁻¹

EXAMPLE 230

1-[3-{2-(3-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3410, 3340, 3240, 1635, 1605 cm⁻¹

EXAMPLE 231

1-[3-{2-(4-Aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3335, 3220, 1635, 1605, 1580 cm⁻¹

EXAMPLE 232

1-[3-{2-(3-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3380, 1685, 1635 cm⁻¹

EXAMPLE 233

1-[3-{2-(4-Acetamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3250, 1685, 1635, 1595 cm⁻¹

EXAMPLE 234

1-[3-{2-(3-Methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3080, 1635, 1610 cm⁻¹

EXAMPLE 235

1-[3-{2-(3-Methoxycarbonylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3260, 1725, 1640 cm⁻¹

EXAMPLE 236

1-[3-{2-(3-Methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 3500, 1635, 1580, 1510 cm⁻¹

EXAMPLE 237

1-[3-{2-(3-Dimethylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine(trans isomer)

IR (Nujol): 1640, 1600 cm⁻¹

EXAMPLE 238

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-methylpiperazinehydrochloride (trans isomer)

IR (Nujol): 2400, 1650, 1580, 1500 cm⁻¹

The following compounds (Examples 239 and 240) were obtained accordingto a similar manner to that of Example 22.

EXAMPLE 239 ##STR107##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-ethylpiperidine(trans isomer)

IR (CHCl₃): 1640, 1590 cm⁻¹

NMR (CDCl₃, δ): 0.90 (3H, t, J=7.5 Hz), 1.10-2.10 (7H, m), 2.20-3.10(2H, m), 3.70-4.20 (2H, m), 6.68 (1H, d, J=18 Hz), 6.85 (1H, t, J=8.0Hz), 7.27 (1H, t, J=8.0 Hz), 7.30-7.54 (3H, m), 7.54-7.82 (3H, m), 7.93(1H, d, J=18 Hz), 8.47 (1H, d, J=8 Hz)

EXAMPLE 240 ##STR108##

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-ethylpiperidine(trans isomer)

IR (CHCl₃): 1635, 1590, 1520 cm⁻¹

NMR (CDCl₃, δ): 0.89 (3H, t, J=6.2 Hz), 1.03-1.47 (4H, m), 1.72 (2H, d,J=11 Hz), 2.78 (2H, t, J=13 Hz), 4.22 (2H, broad), 6.60 (1H, d, J=16Hz), 6.76 (1H, td, J=7 Hz and 1 Hz), 7.06-7.67 (7H, m), 7.82 (1H, d,J=16 Hz), 8.39 (1H, d, J=7 Hz)

MS: 359 (M⁺)

The following compounds (Examples 241 and 242) were obtained accordingto a similar manner to that of Example 62.

EXAMPLE 241

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-ethylpiperidine(trans isomer)

IR (CHCl₃): 1640, 1590 cm⁻¹

EXAMPLE 242

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-ethylpiperidine(trans isomer)

IR (CHCl₃): 1635, 1590, 1520 cm⁻¹

The following compounds (Examples 243 and 244) were obtained accordingto a similar manner to that of Example 25.

EXAMPLE 243

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-3-ethylpiperidine(trans isomer)

IR (CHCl₃): 1640, 1590 cm⁻¹

EXAMPLE 244

1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-4-ethylpiperidine(trans isomer)

IR (CHCl₃): 1635, 1590, 1520 cm⁻¹

EXAMPLE 245 ##STR109##

A solution of(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer) (0.50 g) in methylene chloride (3 ml) was irradiated withsun light by the window and stood for 4 hours. Then the solution wasevaporated in vacuo. The residue was chromatographed on alumina TLC witha mixture of methylene chloride and ethyl acetate (5:1) as an eluent.The parts containing the object compound were combined and extractedwith methylene chloride. The extracts were evaporated in vacuo to give(2R)-1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(cis isomer) (0.15 g) as an oil.

IR (CHCl₃): 1630, 1590, 1520 cm⁻¹

NMR (CDCl₃, δ): 0.73-2.01 (8H, m), 1.70 (1H, s), 2.75 (1H, td, J=13.5 Hzand 3 Hz), 3.00-4.10 (3H, m), 4.52-4.81 (1H, m), 6.08 (1H, d, J=12 Hz),6.78 (1H, td, J=7 Hz and 1 Hz), 6.84 (1H, d, J=12 Hz), 7.06-7.87 (7H,m), 8.41 (1H, d, J=7 Hz)

MS: 375 (M⁺)

EXAMPLE 246 ##STR110##

Ethyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl]acrylate (cis isomer) wasobtained according to a similar manner to that of Example 245.

mp: 54° to 55° C.

IR (Nujol): 1705, 1635 cm⁻¹

NMR (CDCl₃, δ): 1.17 (3H, t, J=7.0 Hz), 4.13 (2H, q, J=7 Hz), 6.05 (1H,d, J=12.0 Hz), 6.50-7.97 (9H, m), 8.48 (1H, dd, J=6.5 Hz)

Analysis Calcd. for C₁₇ H₁₆ N₂ O₂ : C 73.65, H 5.52, N 9.58; Found: C74.24, H 5.92, N 9.49.

EXAMPLE 247 ##STR111##

3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (cis isomer) wasobtained according to a similar manner to that of Example 8.

mp: 153° to 155° C.

IR (Nujol): 1680, 1630, 1600 cm⁻¹

NMR (CDCl₃, δ): 6.15 (1H, d, J=12.0 Hz), 6.70-7.92 (9H, m), 8.53 (1H,dd, J=7.0 Hz and 1.0 Hz), 8.97-9.60 (1H, m)

Analysis Calcd. for C₁₆ H₁₂ N₂ O₂ : C 72.71, H 4.58, N 10.60; Found: C72.87, H 4.67, N 10.58.

EXAMPLE 248 ##STR112##

A solution of(2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine(trans isomer) (0.50 g) in methylene chloride (saturated with HCl gass)(3 ml) was stirred at room temperature. Methylene chloride (saturatedwith HCl gass) (3 ml) was added 4 times to that solution during 7 hours.The reaction mixture was evaporated in vacuo. Tetrahydrofuran (5 ml) wasadded to the residue and stirred. The resulting precipitates werecollected by filtration and dried to give(2R)-2-[2-{3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyloxy}ethyl]piperidinehydrochloride (trans isomer) (0.53 g).

mp: 223.5°-225° C.

IR (Nujol): 1715, 1705, 1620, 1590, 1515 cm⁻¹

NMR (DMSO-d₆, δ): 1.18-3.30 (10H, m), 3.48 (1H, d, J=12 Hz), 4.32 (2H,t, J=6 Hz), 6.25 (1H, d, J=16 Hz), 6.87 (1H, t, J=7 Hz), 7.27-7.90 (7H,m), 7.88 (1H, d, J=16 Hz), 8.50 (1H, d, J=7 Hz)

MS: 375 (M⁺)

[α]_(D) ²⁵.6° =-7.35° (c=1.06, EtOH)

EXAMPLE 249 ##STR113##

2-[2-{3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyloxy}ethyl]piperidinehydrochloride (trans isomer) was obtained according to a similar mannerto that of Example 248.

mp: 217°-220° C.

IR (Nujol): 1715, 1705, 1620, 1590, 1515 cm⁻¹

What we claim is:
 1. A pyrazolopyridine compound of the formula:##STR114## wherein R¹ is lower alkyl, aryl which may be substituted byone or more suitable substituent(s) or a heterocyclic group, R² is agroup of the formula:

    --A--R.sup.6

wherein R⁶ is carboxy or lower alkoxycarbonyl which may be substitutedby a N-containing heterocyclic group; and, A is C₂ -C₆ aliphatichydrocarbon group which may be substituted by one or more halogen atoms;and R³ is hydrogen, lower alkyl, lower alkoxy or halogen, or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1,whereinR¹ is lower alkyl; phenyl which may be substituted by one or moresubstituent(s) selected from halogen, lower alkoxy, nitro, amino, andprotected amino; or unsaturated 3 to 8 membered heteromonocyclic groupcontaining 1 to 4 nitrogen atom(s), and A is C₂ -C₆ alkyl, C₂ -C₆alkenyl or C₂ -C₆ alkynyl, each of which may be substituted by halogenatoms.
 3. A compound of claim 2, whereinR¹ is lower alkyl; phenyl whichmay be substituted by 1 to 3 suitable substituent(s) selected from agroup consisting of halogen, lower alkoxy, nitro, amino, loweralkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino,lower alkylamino and di(lower)alkylamino; or pyridyl.
 4. A compound ofclaim 3, whereinA is C₂ -C₆ alkyl; C₂ -C₆ alkenyl which may besubstituted by halogen atoms or C₂ -C₆ alkynyl.
 5. A compound of claim4, wherein:R⁶ is carboxy or lower alkoxycarbonyl, and A is C₂ -C₆alkenyl which may be substituted by halogen atoms.
 6. The compound ofclaim 5, which is 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acrylic acid.7. A pharmaceutical composition which comprises, as an activeingredient, an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 8. A method for the treatment ofedema, hypertension, renal insufficiency, thrombosis and congestiveheart failure which comprises administering an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof to ahuman or animal.